What's in human blood? Although we don't tend to think of blood as a vast mixing bowl, new research by a scientist at the University of Alberta and others suggests that our blood contains more than 4,000 chemical components.
"Right now a medical doctor analyzing the blood of an ailing patient looks at something like 10 to 20 chemicals," said David Wishart, a biochemist who spent three years on the analysis. "We've identified 4,229 blood chemicals that doctors can potentially look at to diagnose and treat health problems."
Doctors look at blood chemicals or metabolites in order to diagnose such conditions as diabetes and kidney failure. Wishart led more than 20 other researchers at six institutions on the analysis. He called it, "the most complete chemical characterization of blood ever done."
Monday, 28 February 2011
Wednesday, 2 February 2011
CJD diagnosis just got easier
Test for Creutzfeldt–Jakob disease raises hopes of speedier diagnosis.
Tiffany O'Callaghan
In prion diseases such as CJD, an isomer of a prion protein takes on an abnormal shape.
AP Photo/Professors Stanley Prusiner/Fred Cohen, University of California San Francisco Medical SchoolInvasive biopsy is currently the only sure way to diagnose the degenerative neurological condition Creutzfeldt–Jakob Disease (CJD). But a highly sensitive assay could change that, providing a fast, accurate alternative for early diagnosis of this rare but deadly condition.
In its most common form, known as sporadic CJD, the disease affects roughly one in a million people. Beginning in the 1990s, several cases of a variation of CJD known as vCJD were reported among people who had consumed beef from cows infected with another disease, bovine spongiform encephalopathy (BSE).
The findings, published online in Nature Medicine1, also suggest that the assay — developed by microbiologist Ryuichiro Atarashi of Nagasaki University, Japan, and his team — could pave the way for the screening of broad sectors of the population.
CJD is a prion disease, in which an isomer of a common protein known as the prion protein (PrP) takes on an abnormal shape and becomes an infectious variant called PrPSc. This variant is thought to trigger the subsequent malformation of other PrP proteins. Unlike their normal counterparts, PrPSc prions cannot be broken down, and instead accumulate — often clustering in brain tissue.
The pockets of abnormal tissue that result cause brain tissue to develop a sponge-like appearance, and because prion conditions can be spread by affected humans or animals, the diseases are often referred to as transmissible spongiform encephalopathies (TSEs). Humans can be affected by several such conditions, while in addition to BSE in cows, there are several other such disorders among animals, including a condition called scrapie in sheep and hamsters.
No false positives
One problem that has plagued developers of non-biopsy diagnostic techniques is that it is often difficult to avoid false positives among samples taken from patients with neurodegenerative disorders other than CJD.
So Atarashi and his colleagues used a new assay known as a real-time quaking-induced conversion (RT-QUIC) assay. 'Quaking-induced' refers to in vitro shaking, which researchers believe helps to accelerate the reactions, enabling the assay to produce results more quickly.
The team tested cerebrospinal fluid samples from 18 people with CJD and 35 people with other neurodegenerative diseases. This pilot group produced no false positives, and CJD was correctly diagnosed more than 83% of the time.
The researchers compared these results with those obtained using an existing assay that tests for levels of a protein known as 14-3-3, which is a marker for sporadic CJD. When tested on patient samples, the accuracy of 14-3-3 was 72.2%, whereas the specificity was 85.7%.
In a subsequent blind trial on 30 cerebrospinal fluid samples from Australia, RT-QUIC showed 100% specificity, resulting in no false positives among the 14 control samples, and correct diagnoses of 87.5%. 14-3-3 was equally accurate, but the rate of false positives was much higher.
"This technique allows definitive ante-mortem confirmation of CJD," says Atarashi, adding that this is currently difficult because it demands the detection of PrPSc in patients' biopsy specimens.
Supersensitivity
The RT-QUIC assay is also extraordinarily sensitive — detecting the presence of harmful prions at very high dilutions — and speedy, yielding results within 48 hours.
Atarashi first began developing RT-QUIC as a researcher at the National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, in Montana. In 2008, he and his team successfully used it to screen cerebrospinal fluid taken from scrapie-infected hamsters2.
In December, Atarashi co-authored a paper reporting the efficacy of the RT-QUIC assay on nasal secretions and cerebrospinal fluid from hamsters with prion disorders3.
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Byron Caughey, chief of prion/TSE research at the Rocky Mountain lab and a co-author of the two hamster studies, is encouraged by the application of the assay to human cerebrospinal fluid samples. "Of course it will also be important to detect prion diseases in other species, but human diagnosis is of pre-eminent importance," Caughey says.
And although the next step is to replicate the findings in a much larger sample, the promise shown by RT-QUIC in analysing substances other than spinal fluid in hamsters suggests a potentially fertile area for future research in humans. If RT-QUIC could be used to screen blood samples, or cheek or nasal swabs, for example, it could open up the possibilities of much earlier diagnosis and more widespread screening of donated blood.
"The earlier you're able to detect the presence of an infection in humans or animals, the more chance you have of preventing transmission to others and treating the disease in those who are infected," Caughey says.
Tiffany O'Callaghan
In prion diseases such as CJD, an isomer of a prion protein takes on an abnormal shape.
AP Photo/Professors Stanley Prusiner/Fred Cohen, University of California San Francisco Medical SchoolInvasive biopsy is currently the only sure way to diagnose the degenerative neurological condition Creutzfeldt–Jakob Disease (CJD). But a highly sensitive assay could change that, providing a fast, accurate alternative for early diagnosis of this rare but deadly condition.
In its most common form, known as sporadic CJD, the disease affects roughly one in a million people. Beginning in the 1990s, several cases of a variation of CJD known as vCJD were reported among people who had consumed beef from cows infected with another disease, bovine spongiform encephalopathy (BSE).
The findings, published online in Nature Medicine1, also suggest that the assay — developed by microbiologist Ryuichiro Atarashi of Nagasaki University, Japan, and his team — could pave the way for the screening of broad sectors of the population.
CJD is a prion disease, in which an isomer of a common protein known as the prion protein (PrP) takes on an abnormal shape and becomes an infectious variant called PrPSc. This variant is thought to trigger the subsequent malformation of other PrP proteins. Unlike their normal counterparts, PrPSc prions cannot be broken down, and instead accumulate — often clustering in brain tissue.
The pockets of abnormal tissue that result cause brain tissue to develop a sponge-like appearance, and because prion conditions can be spread by affected humans or animals, the diseases are often referred to as transmissible spongiform encephalopathies (TSEs). Humans can be affected by several such conditions, while in addition to BSE in cows, there are several other such disorders among animals, including a condition called scrapie in sheep and hamsters.
No false positives
One problem that has plagued developers of non-biopsy diagnostic techniques is that it is often difficult to avoid false positives among samples taken from patients with neurodegenerative disorders other than CJD.
So Atarashi and his colleagues used a new assay known as a real-time quaking-induced conversion (RT-QUIC) assay. 'Quaking-induced' refers to in vitro shaking, which researchers believe helps to accelerate the reactions, enabling the assay to produce results more quickly.
The team tested cerebrospinal fluid samples from 18 people with CJD and 35 people with other neurodegenerative diseases. This pilot group produced no false positives, and CJD was correctly diagnosed more than 83% of the time.
The researchers compared these results with those obtained using an existing assay that tests for levels of a protein known as 14-3-3, which is a marker for sporadic CJD. When tested on patient samples, the accuracy of 14-3-3 was 72.2%, whereas the specificity was 85.7%.
In a subsequent blind trial on 30 cerebrospinal fluid samples from Australia, RT-QUIC showed 100% specificity, resulting in no false positives among the 14 control samples, and correct diagnoses of 87.5%. 14-3-3 was equally accurate, but the rate of false positives was much higher.
"This technique allows definitive ante-mortem confirmation of CJD," says Atarashi, adding that this is currently difficult because it demands the detection of PrPSc in patients' biopsy specimens.
Supersensitivity
The RT-QUIC assay is also extraordinarily sensitive — detecting the presence of harmful prions at very high dilutions — and speedy, yielding results within 48 hours.
Atarashi first began developing RT-QUIC as a researcher at the National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, in Montana. In 2008, he and his team successfully used it to screen cerebrospinal fluid taken from scrapie-infected hamsters2.
In December, Atarashi co-authored a paper reporting the efficacy of the RT-QUIC assay on nasal secretions and cerebrospinal fluid from hamsters with prion disorders3.
ADVERTISEMENT
Byron Caughey, chief of prion/TSE research at the Rocky Mountain lab and a co-author of the two hamster studies, is encouraged by the application of the assay to human cerebrospinal fluid samples. "Of course it will also be important to detect prion diseases in other species, but human diagnosis is of pre-eminent importance," Caughey says.
And although the next step is to replicate the findings in a much larger sample, the promise shown by RT-QUIC in analysing substances other than spinal fluid in hamsters suggests a potentially fertile area for future research in humans. If RT-QUIC could be used to screen blood samples, or cheek or nasal swabs, for example, it could open up the possibilities of much earlier diagnosis and more widespread screening of donated blood.
"The earlier you're able to detect the presence of an infection in humans or animals, the more chance you have of preventing transmission to others and treating the disease in those who are infected," Caughey says.
Monday, 17 January 2011
Blood Type O Associated With Less Risk for Heart Attack
Executive Health January 17, 2011, 06:00 EST text size: TTBlood Type O Associated With Less Risk for Heart Attack
Study finds gene that raises the danger and another, also tied to blood type, that might offer protectionBy Steven Reinberg
HealthDay Reporter
FRIDAY, Jan. 14 (HealthDay News) -- Researchers have simultaneously discovered a gene that seems to raise the risk of cardiovascular disease, while also noting that having the blood type O might guard against heart attack once arteries become clogged.
"Certain genes predispose to heart artery plaque build-up, whereas different genes lead to heart attack when you already have plaque build-up," said study author Dr. Muredach P. Reilly, an associate professor of medicine at the Cardiovascular Institute of the University of Pennsylvania.
One of the more heart-protective genes also helps direct people to have type O blood, the team reported.
The study suggests the multifaceted relationship between genetics and cardiovascular health, Reilly said. "Not all genes for heart disease are equal and therefore have to be used differently in new treatments for heart disease and when assessing risk of heart disease," he said.
The report is published in the Jan. 15 online edition of The Lancet.
For the study, Reilly's team compared almost 13,000 people with coronary artery disease against almost 7,400 people who did not have the condition.
And to hone in on specific genes that might play a role in heart attacks, they compared about 5,800 people with coronary artery disease who had had a heart attack with more than 3,600 people who had coronary artery disease but had never had a heart attack.
Using this method, Reilly's group identified a new gene called ADAMTS7, which was associated with an increased risk of coronary artery disease.
And in the analysis specific to heart attack, they also found an association between blood type and the risk for heart attacks.
Specifically, the gene that makes people have blood type O also protects them from heart attacks, the researchers explained.
Blood is classified as ABO, with eight possible types, determined by the antigens they carry. Type O is know as the universal red cell donor.
"Therapies that modify ADAMTS7 and blood typing may be useful for heart disease, but are likely to work in different ways and different people," Reilly said.
"This concept speaks to future advances in personalized medicine and heart disease treatments. In addition, blood groups might be simple, if crude, indicators of heart attack risk or protection," he said.
But one expert cautioned that while blood type O may offer some protection from heart attack in people with coronary artery disease, that doesn't mean that your blood type alone will spare you from cardiovascular trouble.
"Individuals with blood type O should be just as vigilant about preventing heart disease and stroke as those of other blood types," said Dr. Gregg Fonarow, a professor of cardiology at the University of California, Los Angeles.
Dr. Luca A. Lotta, co-author of accompanying editorial from the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Luigi Villa Foundation, University of Milan, said the findings "increase our knowledge of the DNA sequences that predispose individuals to develop atherosclerosis and myocardial infarction."
However, there is no direct and immediate clinical application for the findings, she added.
"But, they may lead in the future to the identification of previously unrecognized disease mechanisms and, potentially, to the development of new preventive and therapeutic strategies for these common and severe diseases," Lotta said.
Fonarow noted that, "it is well-established that there are genetic components to the risk of developing coronary atherosclerosis and myocardial infarction."
However, studies have not shown that genetic testing improves risk stratification or has clinical value in determining which treatment should be given over standard care, he said.
More information
For more information on genes and heart disease, visit the American Heart Association.
SOURCES: Muredach P. Reilly, MBBCH, associate professor, medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia; Luca A. Lotta, M.D., Angelo Bianchi Bonomi Hemophia and Thrombosis Center, Luigi Villa Foundation, University of Milan; Gregg Fonarow, M.D., American Heart Association spokesman and professor, cardiology, University of California, Los Angeles; Jan. 15, 2011, The Lancet, online
Study finds gene that raises the danger and another, also tied to blood type, that might offer protectionBy Steven Reinberg
HealthDay Reporter
FRIDAY, Jan. 14 (HealthDay News) -- Researchers have simultaneously discovered a gene that seems to raise the risk of cardiovascular disease, while also noting that having the blood type O might guard against heart attack once arteries become clogged.
"Certain genes predispose to heart artery plaque build-up, whereas different genes lead to heart attack when you already have plaque build-up," said study author Dr. Muredach P. Reilly, an associate professor of medicine at the Cardiovascular Institute of the University of Pennsylvania.
One of the more heart-protective genes also helps direct people to have type O blood, the team reported.
The study suggests the multifaceted relationship between genetics and cardiovascular health, Reilly said. "Not all genes for heart disease are equal and therefore have to be used differently in new treatments for heart disease and when assessing risk of heart disease," he said.
The report is published in the Jan. 15 online edition of The Lancet.
For the study, Reilly's team compared almost 13,000 people with coronary artery disease against almost 7,400 people who did not have the condition.
And to hone in on specific genes that might play a role in heart attacks, they compared about 5,800 people with coronary artery disease who had had a heart attack with more than 3,600 people who had coronary artery disease but had never had a heart attack.
Using this method, Reilly's group identified a new gene called ADAMTS7, which was associated with an increased risk of coronary artery disease.
And in the analysis specific to heart attack, they also found an association between blood type and the risk for heart attacks.
Specifically, the gene that makes people have blood type O also protects them from heart attacks, the researchers explained.
Blood is classified as ABO, with eight possible types, determined by the antigens they carry. Type O is know as the universal red cell donor.
"Therapies that modify ADAMTS7 and blood typing may be useful for heart disease, but are likely to work in different ways and different people," Reilly said.
"This concept speaks to future advances in personalized medicine and heart disease treatments. In addition, blood groups might be simple, if crude, indicators of heart attack risk or protection," he said.
But one expert cautioned that while blood type O may offer some protection from heart attack in people with coronary artery disease, that doesn't mean that your blood type alone will spare you from cardiovascular trouble.
"Individuals with blood type O should be just as vigilant about preventing heart disease and stroke as those of other blood types," said Dr. Gregg Fonarow, a professor of cardiology at the University of California, Los Angeles.
Dr. Luca A. Lotta, co-author of accompanying editorial from the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Luigi Villa Foundation, University of Milan, said the findings "increase our knowledge of the DNA sequences that predispose individuals to develop atherosclerosis and myocardial infarction."
However, there is no direct and immediate clinical application for the findings, she added.
"But, they may lead in the future to the identification of previously unrecognized disease mechanisms and, potentially, to the development of new preventive and therapeutic strategies for these common and severe diseases," Lotta said.
Fonarow noted that, "it is well-established that there are genetic components to the risk of developing coronary atherosclerosis and myocardial infarction."
However, studies have not shown that genetic testing improves risk stratification or has clinical value in determining which treatment should be given over standard care, he said.
More information
For more information on genes and heart disease, visit the American Heart Association.
SOURCES: Muredach P. Reilly, MBBCH, associate professor, medicine, Cardiovascular Institute, University of Pennsylvania, Philadelphia; Luca A. Lotta, M.D., Angelo Bianchi Bonomi Hemophia and Thrombosis Center, Luigi Villa Foundation, University of Milan; Gregg Fonarow, M.D., American Heart Association spokesman and professor, cardiology, University of California, Los Angeles; Jan. 15, 2011, The Lancet, online
Thursday, 13 January 2011
Artificial blood cells breakthrough
Jelly-like synthetic particles which mimic tiny cells in size and shape may be the first step towards developing truly artificial blood, scientists believe.
The "hydrogel" nanoparticles measuring just six micrometres (0.006 millimetres) across could also be used to fight cancer. They have the important property of being highly flexible, just like real red blood cells, and this means they remain longer in the circulation before being filtered out, and can slip through narrow capillaries or microscopic pores in organs.
Scientists are yet to test the particles' ability to perform functions such as transporting oxygen or carrying anti-cancer drugs. But early experiments indicate they have exciting medical potential. One possible application is unlimited supplies of man-made blood.
To date the most promising research on so-called synthetic blood has seen red blood cells created from stem cells.
A US company has developed a "pharming" process to produce blood cells from stem cells taken from umbilical cords which it hopes can be used in the field. Scientists have also succeeded in creating red blood cells from spare IVF embryos, but attempts to mimic nature with an artificial way of carrying oxygen around the body have not proved successful.
Lack of flexibility has been the major stumbling block. Real blood cells gradually become stiffer during their life and are eventually filtered out of the circulation when they can no longer bend enough to pass through pores in the spleen.
Professor Joseph DeSimone, one of the study investigators from the University of North Carolina, said: "Creating particles for extended circulation in the blood stream has been a significant challenge in the development of drug delivery systems from the beginning.
"Although we will have to consider particle deformability along with other parameters when we study the behaviour of particles in the human body, we believe this study represents a real game changer for the future of nanomedicine."
The research has been published in the journal Proceedings of the National Academy of Sciences.
Commenting on the study, US professor Chad Mirkin, from Northwestern University in Chicago and one of US President Barack Obama's science advisers, said: "These findings are significant since the ability to reproducibly synthesise micron-scale particles with tuneable deformability that can move through the body unrestricted as do red blood cells, opens the door to a new frontier in treating disease."
The "hydrogel" nanoparticles measuring just six micrometres (0.006 millimetres) across could also be used to fight cancer. They have the important property of being highly flexible, just like real red blood cells, and this means they remain longer in the circulation before being filtered out, and can slip through narrow capillaries or microscopic pores in organs.
Scientists are yet to test the particles' ability to perform functions such as transporting oxygen or carrying anti-cancer drugs. But early experiments indicate they have exciting medical potential. One possible application is unlimited supplies of man-made blood.
To date the most promising research on so-called synthetic blood has seen red blood cells created from stem cells.
A US company has developed a "pharming" process to produce blood cells from stem cells taken from umbilical cords which it hopes can be used in the field. Scientists have also succeeded in creating red blood cells from spare IVF embryos, but attempts to mimic nature with an artificial way of carrying oxygen around the body have not proved successful.
Lack of flexibility has been the major stumbling block. Real blood cells gradually become stiffer during their life and are eventually filtered out of the circulation when they can no longer bend enough to pass through pores in the spleen.
Professor Joseph DeSimone, one of the study investigators from the University of North Carolina, said: "Creating particles for extended circulation in the blood stream has been a significant challenge in the development of drug delivery systems from the beginning.
"Although we will have to consider particle deformability along with other parameters when we study the behaviour of particles in the human body, we believe this study represents a real game changer for the future of nanomedicine."
The research has been published in the journal Proceedings of the National Academy of Sciences.
Commenting on the study, US professor Chad Mirkin, from Northwestern University in Chicago and one of US President Barack Obama's science advisers, said: "These findings are significant since the ability to reproducibly synthesise micron-scale particles with tuneable deformability that can move through the body unrestricted as do red blood cells, opens the door to a new frontier in treating disease."
Sunday, 9 January 2011
Eat and Exercise for your Blood Type
Ever wondered why your training partner recovers from a workout faster than you, or why you need more fuel on the run than they do? It could be because you have a different blood type.
For more than a decade, runners worldwide have been subscribing to Dr Peter D’Adamo’s Blood Type Diet.
The American naturopathic physician and researcher is author of Eat Right For Your Type, a series of books about eating and exercising for your blood type. His theory? Each of the four basic blood types O, A, B and AB reacts differently to the lectins, or proteins, in the foods we eat.
His research shows each blood type is susceptible to certain diseases, physical vitality and emotional strength, and by adjusting your diet to suit your biological make up, you can live – and run – better.
But Dr Trent Watson, Dietitians Association of Australia spokesperson, says there is little scientific evidence to suggest such strict DNA traits are passed on.
“There are 50,000 to 100,000 genes contained in human DNA, so passing on the same DNA from one generation to the next is like rolling the genetic dice,” says the Newcastle sports dietitian.
Dr Watson suggests runners interested in taking up the Blood Type Diet seek advice from a dietitian to ensure you match nutrition and energy needs with your level of training.
TYPE 0
This is the most common of the four blood types and, according to Dr D’Adamo, your ancestral background shows you are hunters with an extroverted personality type.
He says Type Os can have a higher level of stomach acid than the other blood types, which can result in stomach irritation and ulcers – a theory supported by a 1993 Oxford University study. Dr D’Adamo’s research shows Type Os are more susceptible to arthritis, asthma and hay fever because the immune system is “environmentally intolerant”, especially to foods such as grains and potatoes, which can produce inflammatory reactions in your joints.
EAT RIGHT
Dr D’Adamo’s Type O diet focuses on protein particularly lean, organic meats, vegetables and fruits. He says it’s best to avoid wheat and dairy, which can trigger digestive problems. Caffeine and alcohol can also raise adrenaline and noradrenaline and should be avoided.
TYPE A
Type As are cultivators and more likely to have an introverted personality, according to Dr D’Adamo. You are thought to have high cortisol levels, a hormone made by the adrenal glands which helps maintain blood pressure, immune function and the body's anti-inflammatory processes. Too much of this hormone can lead to heart disease, cancer and diabetes, writes Dr D’Adamo.
EAT RIGHT
Type As are more naturally suited to a vegetarian diet of organic Mediterranean foods. Hopkins recommends avoiding dairy and red meat, because As are typically low in intestinal alkaline phosphatise, a stomach acid, which makes it difficult to digest and metabolise animal protein and fat.
TYPE B
More like nomads with an independent personality, Type Bs have a strong immune system and a tolerant digestive system, says Dr D’Adamo. “They tend to resist many of the severe chronic degenerative illnesses, or at least survive them better than the other blood types,” he writes. But Type B is more susceptible to autoimmune disorders, such as chronic fatigue, lupus and multiple sclerosis because of a reaction to foods that affect how your metabolic process works.
EAT RIGHT
Dr D’Adamo says Type Bs are generally capable of digesting either animal proteins or carbohydrates. But, he says, it’s best to avoid chicken, which contains a lectin in its muscle tissue that can attack the bloodstream. He also recommends avoiding wheat, buckwheat, lentils, tomatoes, peanuts and sesame seeds. “Each of these foods affect the efficiency of your metabolic process, resulting in fatigue, fluid retention and hypoglycemia – a severe drop in blood sugar after eating,” he writes.
TYPE AB
This is the rarest blood type, carried by just two to five per cent of the population. Known for an intuitive personality, Dr D’Adamo says Type ABs are the most biologically complex because group because they combine elements of both blood types. Like Type As, Dr D’Adamo says ABs immune system can be more susceptible to heart disease, cancer and anaemia when under stress.
EAT RIGHT
According to Dr D’Adamo Type AB has Type A’s low levels of stomach acid, but Type B’s adaptation to meats. “Therefore, you lack enough stomach acid to metabolise them efficiently and the meat you eat tends to get stored as fat,” he writes. Hopkins says he has more energy when he eats the right foods including plenty of green vegetables, seafood, dairy and tofu. Dr D’Adamo recommends type ABs avoid smoked or cured meats because they can cause stomach cancer in people with low levels of stomach acid.
For more than a decade, runners worldwide have been subscribing to Dr Peter D’Adamo’s Blood Type Diet.
The American naturopathic physician and researcher is author of Eat Right For Your Type, a series of books about eating and exercising for your blood type. His theory? Each of the four basic blood types O, A, B and AB reacts differently to the lectins, or proteins, in the foods we eat.
His research shows each blood type is susceptible to certain diseases, physical vitality and emotional strength, and by adjusting your diet to suit your biological make up, you can live – and run – better.
But Dr Trent Watson, Dietitians Association of Australia spokesperson, says there is little scientific evidence to suggest such strict DNA traits are passed on.
“There are 50,000 to 100,000 genes contained in human DNA, so passing on the same DNA from one generation to the next is like rolling the genetic dice,” says the Newcastle sports dietitian.
Dr Watson suggests runners interested in taking up the Blood Type Diet seek advice from a dietitian to ensure you match nutrition and energy needs with your level of training.
TYPE 0
This is the most common of the four blood types and, according to Dr D’Adamo, your ancestral background shows you are hunters with an extroverted personality type.
He says Type Os can have a higher level of stomach acid than the other blood types, which can result in stomach irritation and ulcers – a theory supported by a 1993 Oxford University study. Dr D’Adamo’s research shows Type Os are more susceptible to arthritis, asthma and hay fever because the immune system is “environmentally intolerant”, especially to foods such as grains and potatoes, which can produce inflammatory reactions in your joints.
EAT RIGHT
Dr D’Adamo’s Type O diet focuses on protein particularly lean, organic meats, vegetables and fruits. He says it’s best to avoid wheat and dairy, which can trigger digestive problems. Caffeine and alcohol can also raise adrenaline and noradrenaline and should be avoided.
TYPE A
Type As are cultivators and more likely to have an introverted personality, according to Dr D’Adamo. You are thought to have high cortisol levels, a hormone made by the adrenal glands which helps maintain blood pressure, immune function and the body's anti-inflammatory processes. Too much of this hormone can lead to heart disease, cancer and diabetes, writes Dr D’Adamo.
EAT RIGHT
Type As are more naturally suited to a vegetarian diet of organic Mediterranean foods. Hopkins recommends avoiding dairy and red meat, because As are typically low in intestinal alkaline phosphatise, a stomach acid, which makes it difficult to digest and metabolise animal protein and fat.
TYPE B
More like nomads with an independent personality, Type Bs have a strong immune system and a tolerant digestive system, says Dr D’Adamo. “They tend to resist many of the severe chronic degenerative illnesses, or at least survive them better than the other blood types,” he writes. But Type B is more susceptible to autoimmune disorders, such as chronic fatigue, lupus and multiple sclerosis because of a reaction to foods that affect how your metabolic process works.
EAT RIGHT
Dr D’Adamo says Type Bs are generally capable of digesting either animal proteins or carbohydrates. But, he says, it’s best to avoid chicken, which contains a lectin in its muscle tissue that can attack the bloodstream. He also recommends avoiding wheat, buckwheat, lentils, tomatoes, peanuts and sesame seeds. “Each of these foods affect the efficiency of your metabolic process, resulting in fatigue, fluid retention and hypoglycemia – a severe drop in blood sugar after eating,” he writes.
TYPE AB
This is the rarest blood type, carried by just two to five per cent of the population. Known for an intuitive personality, Dr D’Adamo says Type ABs are the most biologically complex because group because they combine elements of both blood types. Like Type As, Dr D’Adamo says ABs immune system can be more susceptible to heart disease, cancer and anaemia when under stress.
EAT RIGHT
According to Dr D’Adamo Type AB has Type A’s low levels of stomach acid, but Type B’s adaptation to meats. “Therefore, you lack enough stomach acid to metabolise them efficiently and the meat you eat tends to get stored as fat,” he writes. Hopkins says he has more energy when he eats the right foods including plenty of green vegetables, seafood, dairy and tofu. Dr D’Adamo recommends type ABs avoid smoked or cured meats because they can cause stomach cancer in people with low levels of stomach acid.
Monday, 13 December 2010
The Blood Type Diet Under the Spotlight
That gives me a good idea, but can you be more specific about what you can and can’t eat?
Each of the four blood types has a detailed list of foods that should be avoided and those that can be included. Here’s the lowdown…
Blood Group O
This is the most common blood group in the UK. Dr D’Adamo says that our digestive tract retains the memory of ancient times, and so type Os need to eat a typical hunter-gatherer type diet. In other words, type Os should follow a high-protein, low-carb diet with lots of meat and fish but no dairy products, wheat or grains.
If that sounds familiar, it’s because it is – the diet recommended for people with blood type O is simply a variation on many of the typical high-protein, low-carb diets that are currently popular, such as the Atkins diet. Foods you can eat freely include meat, fish and olive oil; foods you can eat in moderation include eggs, nuts, seeds, certain vegetables and fruits; and foods to avoid include dairy products, beans, cereals, bread, pasta and rice. To complement your food intake, Dr D’Adamo recommends lots of vigorous aerobic exercise such as aerobics and running – just like our hunter-gatherer ancestors did!
Blood Group A
This is the second most common blood type in the UK. Again according to Dr D'Adamo, digestive system is apparently very good at remembering that our ancestors had settled, farming lifestyles, which included eating lots of grains and vegetables but little meat. Consequently, blood type A’s should follow a vegetarian diet but still avoid dairy products. This means nuts, seeds, beans, cereals, pasta, rice, fruit and veg are all on the ‘to eat’ list. Meanwhile, calming exercises are thought to be best for blood type A’s such as yoga or golf.
Blood Group B
Only one person in 10 has blood type B – a real shame when you consider this blood group has the least dietary restrictions! As our type B ancestors were able to thrive on all sorts of foods, thanks to all that travelling, very few foods need to be avoided and this is the closest you’ll get to a healthy, balanced diet from Dr D'Adamo. The only foods that need to be avoided are processed foods, although nuts and seeds aren’t recommended and only small amounts of carb-rich foods should be eaten. When it comes to exercise, Dr D’Adamo recommends activities that have mental component, such as hiking, tennis and swimming – clearly our ancestors did a lot of thinking while they were walking!
Blood Group AB
People with this rare blood type should eat a combination of the foods recommended for blood groups A and B. Somewhat confusing when type B allows you to eat most foods, while type A suggests a vegetarian diet! Dr D’Adamo gets around this by suggesting that type ABs follow a veggie diet most of the time with some meat, fish and dairy products occasionally. It’s the same when it comes to exercise too – blood type ABs should combine calming exercises with moderately intense activities.
What do the experts say?
Medical experts universally agree that the theory is nonsense, and say there is absolutely no link between our blood group and the diet we eat. Consequently you won’t find qualified nutritionists or dietitians recommending this diet.
There are also several concerns, namely that the diets recommended for blood groups O and A are considerably limited and cut out major groups of foods.
In the long term, this can result in a poor intake of nutrients needed for good health. Cutting out dairy products, for example, will lead to poor intakes of calcium, which can put you at risk of osteoporosis (brittle bone disease), while avoiding meat can result in low intakes of iron, which can lead to anaemia. This is even more worrying in view of the fact that most people in the UK are blood group O or A.
Each of the four blood types has a detailed list of foods that should be avoided and those that can be included. Here’s the lowdown…
Blood Group O
This is the most common blood group in the UK. Dr D’Adamo says that our digestive tract retains the memory of ancient times, and so type Os need to eat a typical hunter-gatherer type diet. In other words, type Os should follow a high-protein, low-carb diet with lots of meat and fish but no dairy products, wheat or grains.
If that sounds familiar, it’s because it is – the diet recommended for people with blood type O is simply a variation on many of the typical high-protein, low-carb diets that are currently popular, such as the Atkins diet. Foods you can eat freely include meat, fish and olive oil; foods you can eat in moderation include eggs, nuts, seeds, certain vegetables and fruits; and foods to avoid include dairy products, beans, cereals, bread, pasta and rice. To complement your food intake, Dr D’Adamo recommends lots of vigorous aerobic exercise such as aerobics and running – just like our hunter-gatherer ancestors did!
Blood Group A
This is the second most common blood type in the UK. Again according to Dr D'Adamo, digestive system is apparently very good at remembering that our ancestors had settled, farming lifestyles, which included eating lots of grains and vegetables but little meat. Consequently, blood type A’s should follow a vegetarian diet but still avoid dairy products. This means nuts, seeds, beans, cereals, pasta, rice, fruit and veg are all on the ‘to eat’ list. Meanwhile, calming exercises are thought to be best for blood type A’s such as yoga or golf.
Blood Group B
Only one person in 10 has blood type B – a real shame when you consider this blood group has the least dietary restrictions! As our type B ancestors were able to thrive on all sorts of foods, thanks to all that travelling, very few foods need to be avoided and this is the closest you’ll get to a healthy, balanced diet from Dr D'Adamo. The only foods that need to be avoided are processed foods, although nuts and seeds aren’t recommended and only small amounts of carb-rich foods should be eaten. When it comes to exercise, Dr D’Adamo recommends activities that have mental component, such as hiking, tennis and swimming – clearly our ancestors did a lot of thinking while they were walking!
Blood Group AB
People with this rare blood type should eat a combination of the foods recommended for blood groups A and B. Somewhat confusing when type B allows you to eat most foods, while type A suggests a vegetarian diet! Dr D’Adamo gets around this by suggesting that type ABs follow a veggie diet most of the time with some meat, fish and dairy products occasionally. It’s the same when it comes to exercise too – blood type ABs should combine calming exercises with moderately intense activities.
What do the experts say?
Medical experts universally agree that the theory is nonsense, and say there is absolutely no link between our blood group and the diet we eat. Consequently you won’t find qualified nutritionists or dietitians recommending this diet.
There are also several concerns, namely that the diets recommended for blood groups O and A are considerably limited and cut out major groups of foods.
In the long term, this can result in a poor intake of nutrients needed for good health. Cutting out dairy products, for example, will lead to poor intakes of calcium, which can put you at risk of osteoporosis (brittle bone disease), while avoiding meat can result in low intakes of iron, which can lead to anaemia. This is even more worrying in view of the fact that most people in the UK are blood group O or A.
Saturday, 11 December 2010
Blood Transfusion in the 21st Century
Projected changes in blood transfusion in the 21st century
1-Universal leukoreduction
2-increasing ise of Apheresis technology to collect blood
3-Microbial attenuation of
acellular blood products
cellular blood products
4-Reconinant plasma proteins
5-Enzymatic conversion of group A,B and AB red celld to group O
6-Oxygen carrying substitues
7-Non liquid ( synthetic) platlets
Tuesday, 9 November 2010
Cellular 'alchemy' transforms skin into blood
Direct conversion of cell types could offer safer, simpler treatments than stem cells.
Ewen Callaway
The right cocktail of chemicals converts human skin cells directly into blood.www.ingrampublishing.comHuman skin cells can be transformed into blood without first being sent through a primordial, stem-cell-like state, according to a ground-breaking study.
The breakthrough, published online today in Nature1, follows work earlier this year showing that fibroblast cells from mouse skin, treated with the right cocktail of chemicals, can be transformed into neurons2 and heart muscle3. However, it is the first study to accomplish this feat with human cells, and the first to create progenitor cells — in this case for blood.
"It takes us a step along the line to believing that you can produce anything from almost anything," says Ian Wilmut, an embryologist and director of the MRC Centre for Regenerative Medicine in Edinburgh, UK. Such 'direct conversions' also offer a potentially safer, simpler tool for creating patient-specific cell therapies than is promised by adult cells reprogrammed to become stem cells (known as induced pluripotent stem cells, or iPS cells).
Mickie Bhatia, a stem-cell researcher at McMaster University in Hamilton, Canada, and his colleagues chose to make blood progenitors from skin cells because red blood cells created from stem cells do not make the adult form of haemoglobin. "Those cells, because they think they're embryonic, make embryonic and fetal blood," he says.
Creating a bloodline To make blood progenitor cells, Bhatia and his team collected skin fibroblasts from several volunteers. They infected the cells with a virus that inserted the gene OCT4, and then grew them in a soup of immune-stimulating proteins called cytokines.
OCT4 is one of a handful of Yamanaka factors used to transform fibroblasts into iPS cells, but Bhatia's team found no evidence that the blood progenitor cells that they had made went through an embryonic state. The cells' gene-expression patterns never resembled those of embryonic stem cells, and the blood progenitor cells didn't cause mice to develop teratomas — tumours that are characteristic of pluripotent cells.
“Everybody has their favourite cell type. There is a lot of this kind of alchemy going on.”
The progenitors did, however, produce all three classes of blood cells — white blood cells, red blood cells and platelets — all of which seemed to function as they should, according to a battery of experiments. The red blood cells made adult haemoglobin, not the fetal form.
The ultimate test would be transplanting the cells into humans, says Bhatia, but that isn't on the cards — at least not yet. "The clinical side is going to be a lot of work," he says. "At least from our estimation, this is the most encouraging result we've seen for using blood cells for cell-replacement therapy."
Sanguine about the possibilities The potential for therapy is very much on the minds of Bhatia and other scientists who are converting cells directly. Because the progenitor cells bypass pluripotency, there is little risk of them forming tumours when implanted into patients, says Wilmut, who is working on creating other progenitor cells in his own lab.
Deepak Srivastava, a developmental biologist and director of the Gladstone Institute of Cardiovascular Disease in San Francisco, California, led the team responsible for making heart muscle from mouse fibroblasts3. He says that directly converted cells could also offer simpler treatments than iPS cells: the fibroblasts that surround the heart could be transformed into new heart muscle using a stent that delivers drugs to reprogram the cells.
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Converted cells aren't without their drawbacks, though. Unlike iPS and embryonic stem cells, they cannot easily multiply in the lab, so producing the large quantities needed for applications such as screening drugs could prove tough, says Wilmut.
Despite lab experiments establishing that the converted blood cells are indistinguishable from adult blood cells, it is still too early to tell whether they will be as good as the real thing once they are inside patients, says George Daley, a stem-cell biologist at Children's Hospital Boston in Massachusetts.
In particular, epigenetic modifications — changes that modify gene expression without altering the DNA sequence — could differ between blood cells produced naturally and those created by direct conversion. "The journey from a zygote to a specialized blood cell is very long. The journey from a fibroblast to a blood cell in a petri dish may take a very different route," says Daley.
Even with these caveats, direct conversion is gaining in popularity. "Everybody has their favourite cell type," says Daley. "There is a lot of this kind of alchemy going on."
References1.Szabo, E. et al. Nature doi:10.1038/nature09591 (2010).
2.Vierbuchen, T. et al. Nature 463, 1035-1041 (2010). | Article | OpenURL | | ChemPort |
3.Ieda, M. et al. Cell 142, 375-386 (2010). | Article | OpenURL
Ewen Callaway
The right cocktail of chemicals converts human skin cells directly into blood.www.ingrampublishing.comHuman skin cells can be transformed into blood without first being sent through a primordial, stem-cell-like state, according to a ground-breaking study.
The breakthrough, published online today in Nature1, follows work earlier this year showing that fibroblast cells from mouse skin, treated with the right cocktail of chemicals, can be transformed into neurons2 and heart muscle3. However, it is the first study to accomplish this feat with human cells, and the first to create progenitor cells — in this case for blood.
"It takes us a step along the line to believing that you can produce anything from almost anything," says Ian Wilmut, an embryologist and director of the MRC Centre for Regenerative Medicine in Edinburgh, UK. Such 'direct conversions' also offer a potentially safer, simpler tool for creating patient-specific cell therapies than is promised by adult cells reprogrammed to become stem cells (known as induced pluripotent stem cells, or iPS cells).
Mickie Bhatia, a stem-cell researcher at McMaster University in Hamilton, Canada, and his colleagues chose to make blood progenitors from skin cells because red blood cells created from stem cells do not make the adult form of haemoglobin. "Those cells, because they think they're embryonic, make embryonic and fetal blood," he says.
Creating a bloodline To make blood progenitor cells, Bhatia and his team collected skin fibroblasts from several volunteers. They infected the cells with a virus that inserted the gene OCT4, and then grew them in a soup of immune-stimulating proteins called cytokines.
OCT4 is one of a handful of Yamanaka factors used to transform fibroblasts into iPS cells, but Bhatia's team found no evidence that the blood progenitor cells that they had made went through an embryonic state. The cells' gene-expression patterns never resembled those of embryonic stem cells, and the blood progenitor cells didn't cause mice to develop teratomas — tumours that are characteristic of pluripotent cells.
“Everybody has their favourite cell type. There is a lot of this kind of alchemy going on.”
The progenitors did, however, produce all three classes of blood cells — white blood cells, red blood cells and platelets — all of which seemed to function as they should, according to a battery of experiments. The red blood cells made adult haemoglobin, not the fetal form.
The ultimate test would be transplanting the cells into humans, says Bhatia, but that isn't on the cards — at least not yet. "The clinical side is going to be a lot of work," he says. "At least from our estimation, this is the most encouraging result we've seen for using blood cells for cell-replacement therapy."
Sanguine about the possibilities The potential for therapy is very much on the minds of Bhatia and other scientists who are converting cells directly. Because the progenitor cells bypass pluripotency, there is little risk of them forming tumours when implanted into patients, says Wilmut, who is working on creating other progenitor cells in his own lab.
Deepak Srivastava, a developmental biologist and director of the Gladstone Institute of Cardiovascular Disease in San Francisco, California, led the team responsible for making heart muscle from mouse fibroblasts3. He says that directly converted cells could also offer simpler treatments than iPS cells: the fibroblasts that surround the heart could be transformed into new heart muscle using a stent that delivers drugs to reprogram the cells.
ADVERTISEMENT
Converted cells aren't without their drawbacks, though. Unlike iPS and embryonic stem cells, they cannot easily multiply in the lab, so producing the large quantities needed for applications such as screening drugs could prove tough, says Wilmut.
Despite lab experiments establishing that the converted blood cells are indistinguishable from adult blood cells, it is still too early to tell whether they will be as good as the real thing once they are inside patients, says George Daley, a stem-cell biologist at Children's Hospital Boston in Massachusetts.
In particular, epigenetic modifications — changes that modify gene expression without altering the DNA sequence — could differ between blood cells produced naturally and those created by direct conversion. "The journey from a zygote to a specialized blood cell is very long. The journey from a fibroblast to a blood cell in a petri dish may take a very different route," says Daley.
Even with these caveats, direct conversion is gaining in popularity. "Everybody has their favourite cell type," says Daley. "There is a lot of this kind of alchemy going on."
References1.Szabo, E. et al. Nature doi:10.1038/nature09591 (2010).
2.Vierbuchen, T. et al. Nature 463, 1035-1041 (2010). | Article | OpenURL | | ChemPort |
3.Ieda, M. et al. Cell 142, 375-386 (2010). | Article | OpenURL
Thursday, 4 November 2010
WHO selects UAE among best five countries in blood transfusion
Dr. Amin Al Amiri, Executive Director for Medical Practices and Licenses at the Ministry of Health and Chair of the Blood Transfusion National Committee, emphasized that the organization lauded the efforts of the UAE in blood transfusion, pointing out that it selected the UAE as one of the best five models in the field of blood transfusion and its role in enhancing the World Blood Donor Day.
The five listed countries are: South Africa, United Kingdom, Thailand, Canada and United Arab Emirates which is the first Arab country and seventh country worldwide that has been selected to host the world blood donators day in 2008. The ceremony was organized under the patronage of His Highness Sheikh Khelifa Bin Zayed Al Nahyan, UAE President.
He also mentioned that the four international organizations "World Health Organization, International Federation for Red Cross and Red Crescent, International Federation for Blood Transfusion and International Blood Donors Association" lauded the efforts of the UAE which led to its nomination as the headquarters for the WHO's Middle Eastern region. This selection was due to the UAE efforts in supporting blood donators and organizing blood donation ceremonies generally.
Dr. Al Amiri lauded the efforts of the other sectors especially the mosques in encouraging the residents to blood donation and the cooperation of the government sector in disseminating awareness campaigns about blood donation and the usage of modern techniques as well as text messages especially the Ministry of Education, Ministry of Social Affairs to encourage students to participate in the activities of the blood donation center and research in Sharjah.
"We would like to thank the social organizations and institutions for their support to the Ministry of Health referring that the ministry's success could not have been accomplished in the field of blood transfusion campaigns and blood donators without their cooperation", he concluded.
WAM/TF
The five listed countries are: South Africa, United Kingdom, Thailand, Canada and United Arab Emirates which is the first Arab country and seventh country worldwide that has been selected to host the world blood donators day in 2008. The ceremony was organized under the patronage of His Highness Sheikh Khelifa Bin Zayed Al Nahyan, UAE President.
He also mentioned that the four international organizations "World Health Organization, International Federation for Red Cross and Red Crescent, International Federation for Blood Transfusion and International Blood Donors Association" lauded the efforts of the UAE which led to its nomination as the headquarters for the WHO's Middle Eastern region. This selection was due to the UAE efforts in supporting blood donators and organizing blood donation ceremonies generally.
Dr. Al Amiri lauded the efforts of the other sectors especially the mosques in encouraging the residents to blood donation and the cooperation of the government sector in disseminating awareness campaigns about blood donation and the usage of modern techniques as well as text messages especially the Ministry of Education, Ministry of Social Affairs to encourage students to participate in the activities of the blood donation center and research in Sharjah.
"We would like to thank the social organizations and institutions for their support to the Ministry of Health referring that the ministry's success could not have been accomplished in the field of blood transfusion campaigns and blood donators without their cooperation", he concluded.
WAM/TF
Sunday, 31 October 2010
Wednesday, 20 October 2010
Blood Group Diet
The blood group diet is said to have originated from two American Naturopaths, Dr James D'Adamo, and his son Dr Peter D'Adamo, who believe that your blood group type is the key to how you burn your calories, which foods you should eat and how you would benefit from certain types of exercise.
They recommend that eating to suit your blood group may, help you to lose weight, help you fight disease, boost your immune system and slow down the ageing process.
It is believed that a chemical reaction occurs between your blood and foods as they are digested. Lectins, a diverse and abundant protein found in food, may be incompatible with your blood group and adverse side effects may occur. The avoidance of these Lectins which can agglutinate (adhere or stick to one another) can be important if your particular cells-determined by your blood type,may react with them.
There are 4 blood types: A, AB, B, and O
Blood Type O
The O blood type was the first blood type to evolve from the hunter-gatherer era around 50,000 BC. Here the diet was high in red meat and virtually void of grains and dairy. The type-O thrives on a meat-eating diet. As the diet is high in animal protein, the type-O requires intense physical exercise to help burn off the meat.
Type-Os are prone to digestive disorders resulting from over-secretion of stomach acid. They can also be more susceptible to arthritis and thyroid disease due to overactive or hyper -immune system.
Wheat and dairy also promote inflammation in this blood type which can trigger an imbalance in the immune system.
Blood type O individuals can gain a significant amount of weight following a high carbohydrate diet, as their bodies cannot properly metabolize these foods.
Blood Type A
Type-A blood group formed when man began to develop an agricultural lifestyle between 25,000 and 15,000 B.C. People with blood type-A do best on a vegetarian diet for weight loss especially the macrobiotic diet.
The type-A individual hardly produces much hydrochloric acid and therefore does poorly on meat and dairy diets such as the Atkins Diet.
Type-As are generally more prone to cancer, diabetes and heart disease, if they do not take charge of their health. The gene for alcoholism is also found in type-As.
Blood Type B
Type B also evolved from the intermingling of blood type O with the blood type A. This occurred between 15,000 and 10,000 B.C due to man traveling further.
As a result, the type-B individual does best on a dairy diet with some meat (no chicken) and few grains.
The type-Bs suffer from the highest incidence of bladder and urinary tract infections. They are also prone to viral diseases when their immune system is compromised.
Since B blood types can metabolize dairy products and most foods, they will usually lose weight effortlessly as long as peanuts, corn, wheat, and lentils are eliminated from the diet.
Blood Type AB
The rarest and newest blood type to evolve (1500 years old) was the AB blood type. This blood type is the most well adapted to a moderate diet. The type-AB individual benefits from both the A and B type diets.
Meat is not as well digested as seafood, dairy, wheat-free grains and soy foods.
The type-ABs are prone to either diseases encountered by the Type-As or the type-Bs. By undergoing further metabolic typing, it can be determined which diseases they are most likely to be vulnerable.
For weight loss and maintaining a healthy weight, AB's do best on seafood, dairy, nuts and grains.
They recommend that eating to suit your blood group may, help you to lose weight, help you fight disease, boost your immune system and slow down the ageing process.
It is believed that a chemical reaction occurs between your blood and foods as they are digested. Lectins, a diverse and abundant protein found in food, may be incompatible with your blood group and adverse side effects may occur. The avoidance of these Lectins which can agglutinate (adhere or stick to one another) can be important if your particular cells-determined by your blood type,may react with them.
There are 4 blood types: A, AB, B, and O
Blood Type O
The O blood type was the first blood type to evolve from the hunter-gatherer era around 50,000 BC. Here the diet was high in red meat and virtually void of grains and dairy. The type-O thrives on a meat-eating diet. As the diet is high in animal protein, the type-O requires intense physical exercise to help burn off the meat.
Type-Os are prone to digestive disorders resulting from over-secretion of stomach acid. They can also be more susceptible to arthritis and thyroid disease due to overactive or hyper -immune system.
Wheat and dairy also promote inflammation in this blood type which can trigger an imbalance in the immune system.
Blood type O individuals can gain a significant amount of weight following a high carbohydrate diet, as their bodies cannot properly metabolize these foods.
Blood Type A
Type-A blood group formed when man began to develop an agricultural lifestyle between 25,000 and 15,000 B.C. People with blood type-A do best on a vegetarian diet for weight loss especially the macrobiotic diet.
The type-A individual hardly produces much hydrochloric acid and therefore does poorly on meat and dairy diets such as the Atkins Diet.
Type-As are generally more prone to cancer, diabetes and heart disease, if they do not take charge of their health. The gene for alcoholism is also found in type-As.
Blood Type B
Type B also evolved from the intermingling of blood type O with the blood type A. This occurred between 15,000 and 10,000 B.C due to man traveling further.
As a result, the type-B individual does best on a dairy diet with some meat (no chicken) and few grains.
The type-Bs suffer from the highest incidence of bladder and urinary tract infections. They are also prone to viral diseases when their immune system is compromised.
Since B blood types can metabolize dairy products and most foods, they will usually lose weight effortlessly as long as peanuts, corn, wheat, and lentils are eliminated from the diet.
Blood Type AB
The rarest and newest blood type to evolve (1500 years old) was the AB blood type. This blood type is the most well adapted to a moderate diet. The type-AB individual benefits from both the A and B type diets.
Meat is not as well digested as seafood, dairy, wheat-free grains and soy foods.
The type-ABs are prone to either diseases encountered by the Type-As or the type-Bs. By undergoing further metabolic typing, it can be determined which diseases they are most likely to be vulnerable.
For weight loss and maintaining a healthy weight, AB's do best on seafood, dairy, nuts and grains.
Not s ingle prescrption
There is not a single prescription drug that offers a "cure" to any ailment.
Friday, 15 October 2010
52 Facts About Blood Donation
1. More than 4.5 million people need blood transfusions each year in the U.S. and Canada.
2. 43,000 pints: amount of donated blood used each day in the U.S. and Canada.
3. Someone needs blood every two seconds.
4. 37% of the U.S. population is eligible to donate blood – less than 10% do annually**.
5. About 1 in 7 people entering a hospital need blood.
6. One pint of blood can save up to three lives.
7. Healthy people who are at least 17 years old (16 with parental consent), and at least 110 pounds may donate whole blood every 56 days. Females receive 53% of blood transfusions; males receive 47%.
8. 94% of blood donors are registered voters.
9. In 1901, Dr. Karl Landsteiner first identified the major human blood groups: A, B, AB and O.
10. People with O- blood are universal donors of red blood cells.
11. People with AB+ blood are universal recipients of red blood cells, and universal donors of plasma.
12. One unit of whole blood can be separated into several components, including red blood cells, plasma, and platelets.
13. Red blood cells carry oxygen to the body's organs and tissues, and live for about 120 days in the circulatory system.
14. Platelets promote blood clotting and give those with leukemia and other cancers a chance to live.
15. Plasma is a pale yellow mixture of water, proteins and salts.
16. Plasma, which is 90% water, makes up 55% of blood volume.
17. Healthy bone marrow makes a constant supply of red cells, plasma and platelets.
18. Blood or plasma that comes from people who have been paid for it cannot be used for human transfusion.
19. Granulocytes, a type of white blood cell, roll along blood vessel walls in search of bacteria to engulf and destroy.
20. White cells are the body's primary defense against infection.
21. Apheresis is a special kind of blood donation that allows a donor to give specific blood components, such as platelets or red blood cells.
22. 42 days: how long most donated red blood cells can be stored.
23. Five days: how long most donated platelets can be stored.
24. One year: how long frozen plasma can be stored.
25. Much of today's medical care depends on a steady supply of blood from healthy donors.
26. 2.7 pints: the average whole blood and red blood cell transfusion.*
27. Children being treated for cancer, premature infants and children having heart surgery may receive blood and platelets during their treatments.
28. Anemic patients may need blood transfusions to increase their red blood cell levels.
29. Cancer, transplant and trauma patients, and patients undergoing open-heart surgery may require platelet transfusions to survive.
30. Sickle cell disease is an inherited disease that affects more than 80,000 people in the U.S., 98% of whom are of African descent.
31. Many patients with severe sickle cell disease receive blood transfusions every month.
32. Over 10 tests are performed on each unit of donated blood.
33. 17% of non-donors cite "never thought about it" as the main reason for not giving blood, while 15% say they're too busy.
34. The #1 reason blood donors say they give is because they "want to help others."
35. Blood centers often run short of types O and B red blood cells.
36. There is no substitute for human blood.
37. If all blood donors gave three times a year, blood shortages would be a rare event (The current average is about two).
38. 46.5 gallons: amount of blood you could donate if you begin at age 17 and donate every 56 days until you are 79 years old.
39. There are four easy steps to donate blood: medical history, a quick physical, donation and snacks.
40. The actual blood donation takes less than 15 minutes. The entire process – from the time you sign in until the time you leave – usually takes under an hour.
41. After donating blood, you replace the fluid in hours and the red blood cells within four weeks. It takes eight weeks to restore the iron lost after donating.
42. You cannot get AIDS or any other infectious disease by donating blood.
43. 10 pints: the amount of blood in the body of an average adult.
44. One unit of whole blood is roughly the equivalent of one pint.
45. Blood makes up about 7% of your body's weight.
46. Newborn babies have about one cup of blood in their bodies.
47. Giving blood will not decrease your strength.
48. Any company, community organization, place of worship or individual may contact their local community blood center to host a blood drive.
49. Roughly half of all blood donations across the U.S. are collected at blood drives.
50. People who donate blood are volunteers and are not paid for their donation.
51. 500,000 Americans donated blood in the days following the events of September 11
52. Blood donation. It's about an hour of your time. It's About Life!
2. 43,000 pints: amount of donated blood used each day in the U.S. and Canada.
3. Someone needs blood every two seconds.
4. 37% of the U.S. population is eligible to donate blood – less than 10% do annually**.
5. About 1 in 7 people entering a hospital need blood.
6. One pint of blood can save up to three lives.
7. Healthy people who are at least 17 years old (16 with parental consent), and at least 110 pounds may donate whole blood every 56 days. Females receive 53% of blood transfusions; males receive 47%.
8. 94% of blood donors are registered voters.
9. In 1901, Dr. Karl Landsteiner first identified the major human blood groups: A, B, AB and O.
10. People with O- blood are universal donors of red blood cells.
11. People with AB+ blood are universal recipients of red blood cells, and universal donors of plasma.
12. One unit of whole blood can be separated into several components, including red blood cells, plasma, and platelets.
13. Red blood cells carry oxygen to the body's organs and tissues, and live for about 120 days in the circulatory system.
14. Platelets promote blood clotting and give those with leukemia and other cancers a chance to live.
15. Plasma is a pale yellow mixture of water, proteins and salts.
16. Plasma, which is 90% water, makes up 55% of blood volume.
17. Healthy bone marrow makes a constant supply of red cells, plasma and platelets.
18. Blood or plasma that comes from people who have been paid for it cannot be used for human transfusion.
19. Granulocytes, a type of white blood cell, roll along blood vessel walls in search of bacteria to engulf and destroy.
20. White cells are the body's primary defense against infection.
21. Apheresis is a special kind of blood donation that allows a donor to give specific blood components, such as platelets or red blood cells.
22. 42 days: how long most donated red blood cells can be stored.
23. Five days: how long most donated platelets can be stored.
24. One year: how long frozen plasma can be stored.
25. Much of today's medical care depends on a steady supply of blood from healthy donors.
26. 2.7 pints: the average whole blood and red blood cell transfusion.*
27. Children being treated for cancer, premature infants and children having heart surgery may receive blood and platelets during their treatments.
28. Anemic patients may need blood transfusions to increase their red blood cell levels.
29. Cancer, transplant and trauma patients, and patients undergoing open-heart surgery may require platelet transfusions to survive.
30. Sickle cell disease is an inherited disease that affects more than 80,000 people in the U.S., 98% of whom are of African descent.
31. Many patients with severe sickle cell disease receive blood transfusions every month.
32. Over 10 tests are performed on each unit of donated blood.
33. 17% of non-donors cite "never thought about it" as the main reason for not giving blood, while 15% say they're too busy.
34. The #1 reason blood donors say they give is because they "want to help others."
35. Blood centers often run short of types O and B red blood cells.
36. There is no substitute for human blood.
37. If all blood donors gave three times a year, blood shortages would be a rare event (The current average is about two).
38. 46.5 gallons: amount of blood you could donate if you begin at age 17 and donate every 56 days until you are 79 years old.
39. There are four easy steps to donate blood: medical history, a quick physical, donation and snacks.
40. The actual blood donation takes less than 15 minutes. The entire process – from the time you sign in until the time you leave – usually takes under an hour.
41. After donating blood, you replace the fluid in hours and the red blood cells within four weeks. It takes eight weeks to restore the iron lost after donating.
42. You cannot get AIDS or any other infectious disease by donating blood.
43. 10 pints: the amount of blood in the body of an average adult.
44. One unit of whole blood is roughly the equivalent of one pint.
45. Blood makes up about 7% of your body's weight.
46. Newborn babies have about one cup of blood in their bodies.
47. Giving blood will not decrease your strength.
48. Any company, community organization, place of worship or individual may contact their local community blood center to host a blood drive.
49. Roughly half of all blood donations across the U.S. are collected at blood drives.
50. People who donate blood are volunteers and are not paid for their donation.
51. 500,000 Americans donated blood in the days following the events of September 11
52. Blood donation. It's about an hour of your time. It's About Life!
Thursday, 14 October 2010
A good formula
Sensitivity (positivity in disease)= TP / TP + FN
Specificity (negativity in health) = TN / TN + FP
Positive predictive value PV+ = TP / TP + FP
Negative predictive value PV- = TN / TN + FN
T True
F False
P Pos
N Neg
Specificity (negativity in health) = TN / TN + FP
Positive predictive value PV+ = TP / TP + FP
Negative predictive value PV- = TN / TN + FN
T True
F False
P Pos
N Neg
Thursday, 7 October 2010
Thursday, 8 July 2010
The relationship between blood groups and disease
Abstract
Top
Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References
The relative contribution of founder effects and natural selection to the observed distribution of human blood groups has been debated since blood group frequencies were shown to differ between populations almost a century ago. Advances in our understanding of the migration patterns of early humans from Africa to populate the rest of the world obtained through the use of Y chromosome and mtDNA markers do much to inform this debate. There are clear examples of protection against infectious diseases from inheritance of polymorphisms in genes encoding and regulating the expression of ABH and Lewis antigens in bodily secretions particularly in respect of Helicobacter pylori, norovirus, and cholera infections. However, available evidence suggests surviving malaria is the most significant selective force affecting the expression of blood groups. Red cells lacking or having altered forms of blood group-active molecules are commonly found in regions of the world in which malaria is endemic, notably the Fy(a–b–) phenotype and the S-s– phenotype in Africa and the Ge– and SAO phenotypes in South East Asia. Founder effects provide a more convincing explanation for the distribution of the D– phenotype and the occurrence of hemolytic disease of the fetus and newborn in Europe and Central Asia.
Introduction
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
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References
Hirszfeld and Hirszfeld1 showed the frequencies of blood groups A and B differ between populations. Their observations raised fundamental questions regarding the causes of these differences, which were eloquently summarized by Mourant et al2(p1):
Were the differences the result of random genetic drift and founder effects, in small populations which later multiplied and stabilized the original, fortuitous, frequencies, or were they the result of natural selection, arising from differences in fitness between the various blood groups, fitnesses which themselves depended upon locally determined features of the external environment?
Mourant et al concluded that "most workers now agree that both processes are operative, but their relative importance remains in question."2
We now have detailed information concerning almost all the genes giving rise to blood group polymorphisms, the structure of the gene products and the antigens themselves, and in many cases functional information sufficient to delineate mechanisms of interaction with external agents.3–5 In addition, studies on the tracking of Y chromosome and mtDNA haplotypes in human populations provide us with unprecedented information concerning the significance of genetic drift and founder effects in determining the genetic background of different world populations.6 Given this new information, it seems an appropriate time to revisit these questions and ask whether we are any nearer understanding the relative importance of natural selection and founder effects in determining the distribution of human blood groups.
Infectious diseases and selection for ABO blood group antigens
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Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
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References
The molecular basis of the ABO blood group system was elucidated in 1990.7 The gene encodes a glycosyltransferase, which transfers N-acetyl D-galactosamine (group A) or D-galactose (group B) to the nonreducing ends of glycans on glycoproteins and glycolipids. The group O phenotype results from inactivation of the A1 glycosyltransferase gene, and the nonreducing ends of the corresponding glycans in group O subjects express the blood group H antigen (Figure 1A). The ABH antigens are not confined to red cells but are widely expressed in body fluids and tissues. The biologic significance of the A/B transferase has not been clearly demonstrated, but it would be expected that loss of this functional protein in group O patients would have some deleterious consequences for patients of this blood type.
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Figure 1. Structure of ABO, H, and Lewis antigens. (A) Structure of ABO and H antigens on human red cells. H antigen formed by the action of FUT1 on oligosaccharide precursor chains in which the terminal D-galactose residue is linked to carbon 4 of the penultimate N-acetyl D-glucosamine residue (type II chain). (B) Structure of Le blood group antigens in bodily secretions. Secretor gene (FUT2) regulates the production of H antigen, which can be converted to A or B antigen if the corresponding active ABO glycosyltransferase is present. The ABH, Leb-active structures are formed on oligosaccharide precursor chains in which the terminal D-galactose residue is linked to carbon 3 of the penultimate N-acetyl D-glucosamine residue (type I chain) If FUT 2 is deficient the Lea active structure predominates.
One of the most significant disease associations described for non-O (subjects of group A, B, or AB) versus O subjects is susceptibility to arterial and venous thromboembolism (VTE).8,9 Non–group O patients have a greater risk of VTE than patients of group O and have greater levels of von Willebrand factor (vWF) and factor VIII.8,10 The risk of VTE is probably related to the level of vWF and factor VIII because patients of group A2 have lower levels of these proteins than A1, B, and AB and have a lower risk of VTE.9 A, B, and H blood group antigens are expressed on N-glycans of vWF and influence the half-life of the protein (10 hours for group O and 25 hours for non-O subjects), providing an explanation for the greater levels in non-O patients.11 These observations raise the possibility that a greater propensity for blood clot formation in non-O patients conferred a survival advantage to early humans. Such an argument has been made for the occurrence of the prothrombotic mutations factor V Leiden and prothrombin 20210G>A, which are commonly found in white humans dated as occurring 20 000 to 24 000 years ago toward the end of the last ice age.12 It is proposed that mutations like factor V Leiden lower the risk of hemorrhage and/or severe infections and thereby the risk of death during pregnancy.13 A similar hypothesis could explain the function of A and B antigens on vWF.
What then was the stimulus that caused the inactivation of this gene and the creation of the group O phenotype, which is so prevalent throughout the world? Evidence supporting the view that blood group O provides a selective advantage against severe malaria has been recently reviewed.14–16 The argument is persuasive. Group O is presumed to have arisen in Africa before the migration of early humans. Severe malaria results in the death of millions each year before they reach child-bearing age, and therefore selects survival genes.17 Experimental support for the hypothesis is provided by Fry et al18 and by Rowe et al.19 Rowe et al19 report reduced rosetting of Plasmodium falciparum isolates from group O Malian children compared with non-O blood groups. Parasitized red cells form rosettes with uninfected red cells and adhere to vascular endothelium, causing vasocclusion and severe disease.
There are other examples of infectious diseases in which the severity of infection can be directly linked to ABO phenotype. The authors of numerous studies have shown that once a person is infected with cholera (Vibrio cholerae strains O1 El Tor and O139) the phenotype group O confers a greater likelihood of severe infections than non-O blood group phenotypes.20 Glass et al21 suggest that the low prevalence of group O and high prevalence of group B in the Ganges Delta in Bangladesh is directly related to selective pressure from cholera. Almost all recent cholera pandemics have emanated from this region of the world.22 Patients of group O were more susceptible in an outbreak of gastrointestinal infections caused by Escherichia coli O157 in Scotland in 1996. A total of 87.5% of patients who died were group O.23
However, suggestions that smallpox selects against A, thereby explaining the high frequency of group A in Europe, and that the low frequency of O in ancient plague centers in Mongolia and the Middle East is also a reflection of selection are not supported by adequate data (Vogel et al [1960], cited in Mourant et al2(p18); Kreiger and Morton24). More recent studies have linked the high frequency of the HIV-1 resistance mutation CCR532 in Europe with protection against smallpox and the Black Death.25 This proposal has also been questioned.26 The mutations AO and CCR32 occurred much earlier in human evolution than the plague and smallpox epidemics of medieval times. As discussed previously, the AO mutation was likely driven by malaria in Africa before the migration of early humans to Europe, and CCR 32 has been described in skeletons from the Bronze Age.25 A combination of selection against infectious diseases, such as plague and smallpox, and genetic drift and founder effects in small populations (resulting from migration patterns of early humans) may ultimately explain the allele frequencies observed today.
The expression of ABH antigens in tissues and body fluids other than blood cells is regulated by the secretor gene (FUT2), which encodes an alpha 1,2-fucosyltransferase capable of transferring L-fucose to carbon 2 of galactose (beta, 1-3) N-acetyl D-glucosamine–containing glycans. In the absence of an active FUT2 gene (nonsecretor), the structure created is the Lea antigen.27 The product of the Le gene is an alpha 1,3/4 fucosyltransferase (FUT3), which transfers L-fucose to carbon 4 of the penultimate N-acetyl-D-glucosamine residue of the same glycans.28 The structure created in tissues by the combined action of FUT2 and FUT3 is the Leb antigen. A and B antigens can only be formed in the tissues of patients with an active FUT2 by the action of alpha-glycosyltransferases capable of transferring N-acetyl D-galactosamine or D-galactose to carbon 3 of the same glycans (Figure 1B). The secretions and tissues of a person with an active FUT2 (a secretor) can express A, B, H, and Leb antigens in those secretions according to the glycosyltransferase genes inherited. In European and African nonsecretors, the homozygous inheritance of a nonsense mutation (G428A) inactivating FUT2 denoted se428 is frequently found (20% of Europeans).29 In the Far East and Pacific regions, the commonest mutation in FUT2 (A385T, se385) causes a single amino acid change (Ile129Phe) in the stem region of the fucosyltransferase, resulting in a 5-fold reduction in active enzyme and a weak Le(a+b+) phenotype.30 Sequencing FUT2 in 732 patients from 39 populations confirmed the widespread occurrence of the se428 allele in Europe, Central Asia, and Africa and the se385 allele in the Far East and Pacific and mapped 2 further se alleles with a more restricted distribution (se302 and se571) to Central and South Asia and Cambodia, respectively.31 Possession of homozygosity for a nonsecretor phenotype has a demonstrable survival advantage for some infectious diseases.
One of the first proven associations of a blood group polymorphism with disease was that between group O and peptic ulceration.32,33 The gastric pathogen H pylori is now known to be a causative agent leading to peptic ulceration and gastric cancer. According to Björkholm et al,34 H pylori has established colonies in the stomachs of approximately one-half the world's population.34 Early studies demonstrated that a South American strain of H pylori P466 bound to blood group O Leb but not ALeb structures on the gastric epithelium, thereby providing a clear explanation for the greater susceptibility of group O secretors.35 More recent studies on strains of H pylori from different parts of the world have shown that not all strains are so specific for O Leb, with many strains from outside South America having binding capabilities for ALeb in addition to OLeb. Nevertheless, these strains have a greater binding affinity for OLeb compared with ALeb (approximately 5-fold [median] greater).36 Sequence analysis of the bacterial surface molecule responsible for binding to gastric epithelium BabA (blood group antigen binding adhesin) from different strains of H pylori showed that Peruvian strains were closely related to Spanish but not to Asian strains, raising the intriguing possibility that the OLeb-specific strains found in South American may have arisen after European colonization of South America in the 16th century and represent adaptation to a population that is almost entirely of the blood group O phenotype.36
Susceptibility to norovirus infection is also closely linked to the expression of ABH and Le antigens in the gastrointestinal tract. Noroviruses are the commonest cause of acute gastroenteritis in humans and are estimated to account for 60% to 85% of all gastroenteritis outbreaks in developing countries.37 They are transmitted by consumption of contaminated food, particularly oysters, which appear able to concentrate the virus, or exposure to contaminated water.37 The pivotal role of secretor status in determining susceptibility to norovirus has been clearly demonstrated by Thorven et al,38 who compared susceptibility to gastroenteritis in patients and medical staff involved in hospital outbreaks in Sweden. The results demonstrated that only those patients homozygous for nonsecretor were protected from infection. Larsson et al39 further demonstrated significantly lower antibody titers to norovirus GGII in nonsecretors compared with secretors. There are many different strains of norovirus, however, and some strains bind to nonsecretor Lea structures and cause symptomatic infection.40,41The variable specificity of different strains for ABH and Leb structures reported reflects a similar diversity to that of the aforementioned H pylori. Evidence for greater susceptibility of secretors to influenza viruses, rhinoviruses, respiratory syncytial virus, and echoviruses has also been presented.42 Reduced risk of HIV type 1 infection was found in Senegalese commercial sex workers with the nonsecretor type.43 Slow disease progression of HIV-1 in nonsecretors was also reported by Kindberg et al.44
Nonsecretors appear more susceptible to infections by Haemophilus influenzae,45 Neisseria meningitidis, and Streptococcus pneumoniae46 and urinary tract infection caused by E coli.47
A mutation (F508) in the cystic fibrosis transmembrane regulator gene (CFTR) is common in European patients and was present in Europe during the Paleolithic period more than 10 000 years ago.48The possibility that differences in A, B, and H antigen expression in the airway mucus might lead to differences in microbial binding and predispose to more severe lung disease was investigated in 808 patients homozygous for F508. No association with ABO, Se, or Le genotype was observed.49
Rh blood groups and the origin of hemolytic disease of the fetus and newborn
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
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References
The major clinical disease associated with the Rh blood group system is hemolytic disease of the fetus and newborn (HDFN). HDFN usually arises when a mother who is blood group D– carries a fetus who is blood group D+, and fetal red cells released into the maternal circulation immunize the mother to make antibody to D, which traverses the placenta and damages the fetus. Before the introduction of a successful prophylactic treatment in 1968, the frequency of the disease in England and North America was approximately 1 per 170 births.3 Recognition of the disease as a single entity was slow to emerge. In severe cases anti-D crosses the placenta and causes death of the fetus in utero, a condition known as hydrops fetalis. More commonly, disease occurs in the neonatal period, where severe and acute anemia and severe jaundice is fatal, a condition known as icterus gravis neonatorum. Roberts50 cites an account of Louyse Bourgeois, a midwife of Marie de Medici, who published in 1609 what is probably the earliest account of hydrops fetalis in one twin and neonatal jaundice in the other and credits Auden (1905) with several key observations relating to neonatal jaundice, in particular its appearance in successive children of the same parents. The recognition that hydrops fetalis and neonatal jaundice were manifestations of the same disease gradually emerged during the 1920s, and anti-D was shown to be the causative agent in 1939.51
There is now a formidable body of evidence to support the hypothesis that humans originated in Africa and to inform the timescale of various migrations from Africa, which have led to the world populations we have today.6 Simply by overlaying the known distribution of blood group frequencies on the world map of human migrations, the potential significance of genetic drift and founder effects is apparent. Wells6 argues, for example, that it is possible to account for all of the mtDNA and Y-chromosome types in Native Americans with a founding population of 10 to 20 people. Little wonder then that Native Americans are almost exclusively blood group O52 or that the Dia blood group polymorphism tracks the migration of humans from East Asia to the Americas.52 The occurrence of the Dia antigen in South East Poland also provides a measure of the extent to which the Mongol invasions penetrated Europe in more recent times.53,54
In Europe a similar founder effect can be invoked to explain the high frequency of the D– phenotype. The emergence of Paleolithic ancestors surviving the last ice age from refuges in the Basque region of Northern Spain and Southern France and the Ukraine 10 000 to 15 000 years ago and subsequent interbreeding of these survivors with Neolithic migrants from the Middle East provides an explanation for the occurrence of HDFN. To explain the high frequency of the D– allele in Europe, Mourant55 proposed a mixing of 2 populations, one essentially D– and the other D+. He noted that D– frequency was very high in the Basques and postulated the mixing of Paleolithic peoples from the Basque region with Neolithic migrants as the cause. This hypothesis has been largely ignored in the succeeding years, but recent observations made with the use of mtDNA and Y-chromosome markers have led to wide acceptance of the population-mixing hypothesis (Figure 2).52,56–58
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Figure 2. Paleolithic settlers from the last glacial maximum may be the source of the high frequency of D– allele in Europeans. (Top) European location of Paleolithic refuges at the time of the last glacial maximum. Note migration of population containing marker M173 (from Gibbons58; reprinted with permission from American Association for the Advancement of Science). (Bottom) Distribution of the D– allele in Europe (from Mourant et al52; reprinted by permission of Oxford University Press).
Tracking of haplotypes emerging from the Basque and Ukrainian refuges has shown that these populations migrated throughout Europe and Central Asia and into India and Pakistan.59 HDFN is found in all these regions. Mourant55 also suggested a link between the Basques and the Berbers of North Africa because of the high frequency of D– phenotypes among Berbers. This hypothesis is now supported by evidence from maternal DNA markers showing that ancestral Berbers occupied the Basque refuge area and migrated back into North Africa.60 In Western Europe, the D– phenotype results from a complete deletion of RHD.61 The molecular basis of D– phenotype has not been formally determined for Ukrainian D– people. Loss of RhD protein does not appear to be of significant detriment to red cell function. The best available structural models for RhD protein and its homologue RhCE protein indicate they do not function as transport proteins but rather serve to facilitate the assembly of the band 3 protein gas transport complex in the red cell membrane. These observations suggest there is considerable functional redundancy, with D and CE proteins effectively substituting for each other (Figure 3).62
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Figure 3. Structure of the human red cell membrane showing the major surface proteins and minor proteins Fy and CR1. Two major membrane complexes linked to the underlying red cell skeleton are depicted. The Band 3 complex containing glycophorins A (GPA) and B (GPB) and Rh proteins, Rh-associated protein (RhAG), CD47, LW glycoprotein (intercellular adhesion molecule–4), and the junctional complex comprising glycophorins C and D (GPC, GPD), Kell glycoprotein, XK glycoprotein, and Duffy (Fy) glycoprotein. Aquaporin 1 (AQP1), the glucose transporter (GLUT1), decay accelerating factor (DAF, CD55), and complement receptor 1 (CR1) are also shown. ABH active oligosaccharides known to be present on all major surface proteins except Rh proteins are not depicted.
A counterargument to the population mixing hypothesis would be provided by a clear demonstration of selection for D– phenotype by environmental factors. In a thorough review of early studies seeking to identify associations between the D polymorphism and diseases, Mourant et al2 revealed no convincing associations. More recently, 2 studies have reported an association of the D polymorphism with disease. Busquets et al,63 in a study from Barcelona, reported an increased incidence of biliary complications in transplant recipients of livers mismatched for D. The presence of biliary complications in D-nonidentical graft-host cases (23 [30%] of 76) was greater than in D-identical grafts (47 [17%] of 269). Rh polypeptides are not expressed in liver,64 and therefore the mechanism of such an association is not clear. The fact that the study took place in the Basque region of Spain, where the D– phenotype is very common and may result from ancestral Paleolithic settlements, may be very relevant to the interpretation of these findings because it raises the possibility that other genes more relevant to transplantation and also occurring more commonly in Basques than in other populations may be influencing the results. In this context it is interesting to note evidence that donor human leukocyte antigen C (HLA-C) genotype has a profound impact on the outcome of liver transplants.65 HLA-C is the major inhibitory ligand for killer cell immunoglobulin-like receptors (KIRs). KIR genes are highly polymorphic and are expressed on natural killer cells and a subset of T lymphocytes.66,67 Several KIR genes (KIR2DS5, KIR3DS1, KIR2DL2) are significantly different in frequency in Basques, and 3 novel haplotypes were identified by Santin et al.68
Flegr et al69 in a study from the Czech Republic report an association of the polymorphism with Toxoplasma gondii infection whereby subjects (military conscripts) with the D– phenotype who were infected with T gondii (11 [6.08%] of 181) had slower reaction times and consequently were involved in more road traffic accidents than D+ patients infected with T gondii (17 [2.4%] of 709). Rh D protein is not reported to be expressed in brain; therefore, the likely mechanism of such an association is obscure, and given the small numbers of T gondii-infected patients involved in the study, a much larger cohort study will be required to prove the validity of this association.
Considering the evidence thus far, it appears most likely that the frequency of D+ and D– negative phenotypes in Europe and Central Asia is a reflection of genetic drift and migration rather than natural selection, with the early colonists of Europe emerging from Africa with a deletion of RHD (Figure 2). There remains the possibility the original stimulus driving this deletion occurred in Africa as a result of selection. The concomitant occurrence of the D– phenotype in African populations resulting from a different molecular mechanism70,71 may be suggestive of some ancient selective pressure.
Malaria: evidence for selection of blood group phenotypes that are rare outside areas in which malaria is endemic
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Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
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References
It appears likely that the most devastating effects of malaria on human populations coincided with a change of lifestyle from hunter gatherer to more sedentary agricultural practices circa 10 000 years ago.15 The clearance of trees from forest areas created the potential for pools of stagnant water and breeding grounds for the mosquitoes carrying parasites.
The clearest examples of selection in the face of malaria are reflected in the widespread distribution of inherited anemias, particularly sickle cell anemia and alpha thalassemia and the occurrence of hemoglobin C in regions of the world where malaria is endemic.72,73 The mutation giving rise to sickle cell disease (SCD; HbS) may have arisen at 3 different sites in Africa (Atlantic West Africa, Central West Africa, and Bantu-speaking Central and Southern Africa) with expansion of the mutation occurring 2000 to 2500 years ago.74 In this case, patients who inherit an HbS gene from both parents have SCD, whereas those who are heterozygous inheriting the HbS gene from 1 parent and the normal HbA gene from the other parent have substantial protection against malaria. A similar protective effect for the heterozygote seems likely in South East Asia, where HbE is very common and red cells from patients of genotype HbAE are markedly less susceptible to malaria parasite invasion in vitro.75
Further illustrations of the diversity of mutations that have arisen in response to malaria are deficiency of glucose-6 phosphate dehydrogenase, which is widespread in Mediterranean and India,72 and a polymorphism in the promoter of inducible nitric oxide synthase.76
Plasmodium vivax and the blood group Fy(a–b–) phenotype
Complete absence from red cells of the molecule carrying the Duffy blood group antigens (aka DARC) is found in almost 100% of West Africans, and this absence is clearly and unambiguously demonstrated to provide protection from P vivax.77 The molecular basis of this Duffy deficiency is a point mutation in the binding site for the transcription factor GATA-1.78 GATA-1 is a DNA-binding protein essential for erythropoiesis, and its failure to bind to the Duffy gene promoter means that the Duffy protein is absent from the red cells of affected subjects. In Africans the mutation occurs on a Duffy allele that would otherwise generate a Fy(b+) phenotype. The same GATA-1 mutation appears to have occurred on a second occasion in South East Asia, where it occurs on a Duffy allele that would otherwise generate a Fy(a+) phenotype.79 Another mutation creating weak expression of Duffy (Fyx) may also be relevant to malaria, but relevant population studies have not been reported.80 Recently, evidence for the emergence of P vivax strains capable of invading Fy(a–b–) red cells has emerged in South America and East Africa.81,82
The protective effect of the Fy(a–b–) phenotype against P vivax is clear and unambiguously established. Not so clear are any deleterious consequences of this mutation for the subjects expressing the phenotype. Duffy protein is expressed on endothelial cells in these subjects but not on red cells,83 so any attempt to understand the consequences of red cell Duffy deficiency must take account of the functional role of endothelial Duffy. The Duffy protein is a member of the 7 membrane-spanning chemokine receptor family (Figure 3) but unlike most chemokine receptors does not effect intracellular signaling through G proteins. It binds several proinflammatory chemokines of both the CXC and CC subfamilies but does not bind homeostatic chemokines.84 Recent evidence suggests Duffy protein on endothelial cells binds chemokines and facilitates leukocyte extravasation contributing to disease pathogenesis through inflammation.85 Evidence for up-regulation of Duffy expression in the vascular endothelium during infection and transplant rejection supports this view.86,87
The lack of Duffy on red cells in Fy(a–b–) patients alters the balance of proinflammatory chemokines in the body because the very large capacity of red cell binding is absent but the consequences of this change are presently unclear. Lee et al88 provide evidence that red cell and endothelial Duffy regulate the kinetics of chemokine bioavailability between the circulation and extravascular sites during inflammation. Clearly this regulation would be altered in Fy(a–b–) subjects. In a mouse model, inflammation induced by polycytidylic acid significantly enhanced alloimmunization to red cells.89 In this context it is interesting to note that patients with SCD are predominantly of the Fy(a–b–) phenotype and that the production of multiple red cell alloantibodies upon transfusion (usually with blood from white donors) is a frequent and significant problem encountered by employees of blood banks seeking to provide compatible blood for the patients (reviewed in Anstee90). SCD patients in sickle cell crisis and mouse models of human SCD have many indicators of an inflammatory response.91 These data suggest that the enhanced propensity for alloimmunization in SCD patients is related to inflammation and also pose the question as to the significance of Fy(a–b–) in this process. Are Fy(a–b–) SCD patients more likely to make alloantibodies in response to transfusion than SCD patients of normal Fy phenotype? Is there a link between regulation of proinflammatory chemokine availability by red cell Fy and the adaptive immune response?
The data of Afenyi-Annan et al92 provide evidence that SCD patients with the Fy(a–b–) phenotype are more susceptible to chronic organ damage and proteinuria than SCD patients of normal Fy phenotype and are consistent with such an hypothesis. Interpretation is likely also influenced by genetic differences of immune response and cytokine genes in African populations compared with other world populations,93,94 but the genetic backgrounds of SCD patients with normal and Fy(a–b–) phenotype may be sufficiently comparable to allow conclusions regarding alloimmunization and the role of Fy to be drawn. Should Fy(a–b–) subjects be more susceptible to alloimmunization, then the potential use anti-inflammatory therapies in the treatment of vaso-occlusion95,96 may have the added bonus of reducing rates of red cell alloimmunization and provide a much needed alternative approach to a major transfusion problem.
A further consequence of selection for the Fy(a–b–) phenotype in Africa may be to alter the kinetics of HIV-1 infection in those with this phenotype. Several HIV-1 strains bind to Duffy on normal red cells, facilitating the transfer of HIV-1 to its target cells (CD4+/CCR5+ T lymphocytes) with 5- to 12-fold greater efficiency than Fy(a–b–) red cells.97 He et al97 calculate that patients with the Fy(a–b–) phenotype have a 40% greater likelihood of acquiring HIV than those lacking the phenotype; however, the disease, once acquired, has a slower progression than in infected patients of normal Fy type. They conclude that these differences are related to loss of competition for binding HIV-1 between plasma chemokine CCR5 and Duffy on red cells in Fy(a–b–) subjects and consequent changes in the inflammatory state those infected. The findings of this study have been contested by Walley et al,98 who used different methodology to analyze a different cohort of HIV+ and HIV– African American subjects and found no association between Fy genotype and progression to AIDS or risk for HIV acquisition. They also point out that the number of HIV– patents used by Walley et al98 was much smaller (227 vs 814) and suggest this difference may be a major factor affecting the analysis.99
Different strains of P falciparum use different blood group proteins as receptors
The dual availability of in vitro culture systems to study the invasion of human red cells by P falciparum and well-characterized rare blood group phenotypes made it possible to identify red cell receptors used by different parasite strains. Early studies on cells lacking Glycophorin A (Ena– cells100) and glycophorin B (S-s– cells101) provided evidence that these sialic acid–rich red cell-surface glycoproteins were parasite receptors and these observations have been confirmed.102–105 Glycophorins C (GPC) and D (Ge– red cells) are also receptors for some strains of P falciparum.106–108 Glycophorins are major proteins at the red cell surface (Figure 3). Glycophorin A (GPA) and the major anion transport protein (AE1, Band 3) with approximately 106 copies/red cell are the most abundant red cell surface proteins with glycophorins B, C, and D together accounting for a further 450 000 copies per red cell.109,110
Perhaps surprisingly, there is little experimental evidence to suggest selection against the expression of GPA has occurred in response to P falciparum infection. Red cells from patients having the hybrid GPA-GPB protein Dantu, which is common in certain parts of Africa, are reported to resist invasion,111 and it has been suggested that elevated expression of Band 3 occurring in patients with the GPB-GPA-GPB MiIII protein common in South East Asia may be relevant to malaria survival.112 The importance of sialic acid on GPA in forming a receptor for P falciparum102 suggests that red cells expressing glycosylation variants of GPA found commonly in Africans in which N-acetyl D-glucosamine is present in some of the sialic acid–rich O-glycans at the N-terminus (patients with the M1 antigen113) may be relevant to one's susceptibility to malaria.
In contrast to the situation with GPA, subjects lacking glycophorin B are found in high frequency in central Africa.105 Patients with red cells lacking GPC and glycophorin D (Ge–, Leach phenotype) are very rare, but those with Ge– red cells having an altered GPC resulting from deletion of exon 3 of GYPC114,115 are common in Melanesians, most notably in Papua New Guinea, and the resulting phenotype provides protection against P falciparum (Figure 4).72,108 Clearly, different strains of P falciparum target glycophorins associated with one or other of the membrane complexes, providing key cytoskeletal linkages maintaining the stability of the red cell membrane (Figure 3) and selection, resulting in loss or alteration of glycophorins in either of these sites confers a survival advantage.
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Figure 4. Distribution of rare blood group phenotypes selected by malaria in Africa and South East Asia. The location of rare blood group phenotypes lacking glycophorin B (S-s–), having altered glycophorin C (Ge–; Gerbich-negative), Fy (Duffy) blood group–null allele (Fy), Sl(a–) allele of complement receptor 1 (CR1), and the Band 3 mutation causing South East Asian ovalocytosis (SAO) in comparison with the distribution of HbS and HbE alleles.72
Melanesians also exhibit another example of selection, affording protection against cerebral malaria, a phenotype known as South East Asian ovalocytosis. South East Asian ovalocytosis cells, as the name implies, have an abnormal shape. They are also characterized by weakened expression of a large number of blood group antigens, including antigens found on Band 3, GPA, and the Rh blood group proteins.116 In this case selection favors the heterozygote. Heterozygotes inherit a normal Band 3 gene together with a mutant inactive Band 3 gene resulting from a deletion, causing a loss of 9 amino acids at the point at which the cytoplasmic N-terminal domain enters the cytosolic face of the lipid bilayer (reviewed in Bruce117). Homozygous inheritance of this mutation would result in total Band 3 deficiency. Because Band 3 is essential for respiration (Cl/HCO3 exchange) and for maintaining the integrity of the red cell membrane, it must be assumed in evolutionary terms that such an inheritance is incompatible with survival. Rare subjects with total Band 3 deficiency states have been described, but survival depends on extensive medical support, particularly in the neonatal period.118
Complement receptor 1 (CR1; Figure 3) carries antigens of the Knops blood group system. CR1 expression is very variable between patients and red cells expressing fewer than 100 copies CR1 per cell show reduced rosetting with P falciparum strain R29R, as do red cells expressing the Sla– blood group phenotype. The Sla– phenotype, which results from a single nucleotide polymorphism (R1601G) in long homologous repeat D, occurs in only 1% of the white population but reaches 70% in Malians.119–121
Conclusions
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References
The significance of human blood groups can now be seen more clearly in the context of population movement, and the constant battle between humans and infectious disease. Evidence for selection by infectious diseases at the level of the ABO and secretor genes is persuasive but for other blood group antigens, founder effects appear more likely to account for the distribution of blood group polymorphisms except that is, in parts of the world in which malaria is endemic. Available data suggest survival from malaria has been the most significant selective force acting on the blood groups.
Rare blood group phenotypes revealed through compatibility testing in transfusion centers and blood banks throughout the world have provided powerful tools with which to investigate the mechanisms whereby malarial parasites invade human red cells. However, a comprehensive study of the distribution of known blood group polymorphisms in areas in which malaria is endemic has not been undertaken. Now that almost all the blood group genes have been cloned and the molecular bases of most antigens determined, it is feasible to conduct such a study with the use of high-throughput DNA-based methods.122–125 Furthermore, the availability of rapid DNA sequencing methodologies presages an era in which mass screening of genes encoding red cell membrane proteins could be used to identify new polymorphisms of relevance to malarial invasion. Studies of this type, focused in tropical Africa, South East Asia, and Latin America, would provide a valuable database of new information about blood group diversity in populations inhabiting these regions not only for malarial epidemiologists but also for those investigating human susceptibility to new emerging infectious diseases given that zoonoses from wildlife in these regions have been identified as the most significant growing threat to global health of all emerging infectious diseases.126
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References
Contribution: D.J.A. wrote the manuscript.
Conflict-of-interest disclosure: The author declares no competing financial interests.
Correspondence: David Anstee, Bristol Institute for Transfusion Sciences, NHS Blood and Transplant, Bristol, BS34 7QG United Kingdom; e-mail: david.anstee@nhsbt.nhs.uk .
Acknowledgments
The author thanks Lesley Bruce of the Bristol Institute for Transfusion Science for preparing Figure 3, David Briggs of NHS Blood and Transplant for helpful discussions regarding HLA-C and KIR receptors, and Geoff Daniels of the Bristol Institute for Transfusion Science for critical reading of the manuscript.
The author's work is supported by Department of Health (England).
Footnotes
Submitted January 21, 2010; accepted February 18, 2010.
Prepublished online as Blood First Edition Paper, March 22, 2010 DOI: 10.1182/blood-2010-01-261859
References
Top
Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References
1.Hirszfeld L, Hirszfeld H. Serological differences between the blood of different races. Lancet. 1919;197:675–679.
2.Mourant AE, Kope AC, Domaniewska-Sobczak K. Blood Groups and Diseases. Oxford, United Kingdom: Oxford University Press; 1978.
3.Klein HG, Anstee DJ, eds. Mollison's Blood Transfusion in Clinical Medicine (11th ed). Oxford, United Kingdom: Blackwell Science; 2005.
4.Daniels GL. Human Blood Groups (2nd ed). Oxford, United Kingdom: Blackwell Science; 2002.
5.Williams TN. Human red cell polymorphisms and malaria. Curr Opin Microbiol. 2006;9:388–394.[CrossRef][Medline] [Order article via Infotrieve]
6.Wells S. The Journey of Man: A Genetic Odyssey. Princeton, NJ: Princeton University Press; 2002.
7.Yamamoto F, Clausen H, White T, et al. Molecular genetic basis of the histo-blood group ABO system. Nature (Lond). 1990;345(6272):229–233.[CrossRef][Medline] [Order article via Infotrieve]
8.Jenkins PV, O'Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all? Transfusion. 2006;46(10):1836–1844.[CrossRef][Medline] [Order article via Infotrieve]
9.Trégouët D-A, Heath S, Saut N, et al. Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach. Blood. 2009;113(21):5298–5303. [Abstract/Free Full Text]
10.Kamphuisen PW, Eikenboom JCJ, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol. 2001;21(5):731–738. [Free Full Text]
11.Gallinaro L, Cattini MG, Sztukowska M, et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood. 2008;111(7):3540–3545. [Abstract/Free Full Text]
12.Zivelin A, Mor-Cohen R, Kovalsky V, et al. Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago. Blood. 2006;107(12):4666–4668. [Abstract/Free Full Text]
13.Lindqvist PG, Dahlback B. Carriership of factor V Leiden and evolutionary selection advantage. Curr Med Chem. 2008;15(15):1541–1544.[CrossRef][Medline] [Order article via Infotrieve]
14.Cserti CM, Dzik WH. The ABO blood group system and Plasmodium falciparum malaria. Blood. 2007;110(7):2250–2258. [Abstract/Free Full Text]
15.Loscertales MP, Owens S, O'Donnell J, et al. ABO blood group phenotypes and Plasmodium falciparum malaria: unlocking a pivotal mechanism. Adv Parasitol. 2007;65:1–50.[CrossRef][Medline] [Order article via Infotrieve]
16.Rowe JA, Opi DH, Williams TN. Blood groups and malaria: fresh insights into pathogenesis and identification of targets for intervention. Curr Opin Hematol. 2009;16(6):480–487.[CrossRef][Medline] [Order article via Infotrieve]
17.Rich SM, Leendertz F, Xu G, et al. The origin of malignant malaria. Proc Natl Acad Sci U S A. 2009;106(35):14902–14907. [Abstract/Free Full Text]
18.Fry AE, Griffiths MJ, Auburn S, et al. Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria. Hum Mol Genet. 2008;17(4):567–576. [Abstract/Free Full Text]
19.Rowe JA, Handel IG, Thera MA, et al. Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting. Proc Natl Acad Sci U S A. 2007;104(44):17471–17476. [Abstract/Free Full Text]
20.Harris JB, Khan AI, LaRocque RC, et al. Blood group, immunity, and risk of infection with Vibrio cholerae in an area of endemicity. Infect Immun. 2005;73(11):7422–7427. [Abstract/Free Full Text]
21.Glass RI, Holmgren J, Haley CE, et al. Predisposition for cholera of individuals with O blood group. Possible evolutionary significance. Am J Epidemiol. 1985;121(6):791–796. [Abstract/Free Full Text]
22.Kaper JB, Morris JG, Levin MM. Cholera. Clin Microbiol Rev. 1995;8(1):48–86. [Abstract/Free Full Text]
23.Blackwell CC, Dundas S, James VS, et al. Blood group and susceptibility to disease caused by Escherichia coli O157. J Infect Dis. 2002;185(3):393–396.[CrossRef][Medline] [Order article via Infotrieve]
24.Azevêdo E, Kreiger H, Morton NE. Smallpox and the ABO blood groups in Brazil. Am J Hum Genet. 1964;16:451–453.[Medline] [Order article via Infotrieve]
25.Duncan SR, Scott S, Duncan CJ. Reappraisal of the historical selective pressures for the CCR5-delta32 mutation. J Med Genet. 2005;42(3):205–208. [Abstract/Free Full Text]
26.Cohn SK Jr, Weaver LT. The Black Death and AIDS: CCR5 delta 32 in genetics and history. Q J Med. 2006;99(8):497–503.
27.Oriol R, Danilovs J, Hawkins BR. A new genetic model proposing that the Se gene is a structural gene closely linked to the H gene. Am J Hum Genet. 1981;33(3):421–431.[Medline] [Order article via Infotrieve]
28.Kukowska-Latallo JF, Larsen RD, Nair RP, et al. A cloned human cDNA determines expression of a mouse stage-specific embryonic antigen and the Lewis blood group alpha(1,3/1,4) fucosyltransferase. J Biol Chem. 1990;4(8):1288–1303.
29.Kelly RJ, Rouquier S, Giorgi D, et al. Sequence and expression of a candidate for the human secretor blood group alpha (1,2) fucosyltransferase gene (FUT2): homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. J Biol Chem. 1995;270(9):4640–4649. [Abstract/Free Full Text]
30.Henry S, Mollicone R, Fernandez P, et al. Molecular basis for erythrocyte Le(a+b+) and salivary ABH partial secretor phenotypes: expression of a FUT2 secretor allele with an A>T mutation at nucleotide 385 correlates with reduced alpha(1,2)fucosyltransferase activity. Glycocon J. 1996;13(6):985–993.[CrossRef][Medline] [Order article via Infotrieve]
31.Ferrer-Admetlla A, Sikora M, Laayouni H, et al. A natural history of FUT2 polymorphism in humans. Mol Biol Evol. 2009;26(9):1993–2003. [Abstract/Free Full Text]
32.Aird I, Bentall HH, Mehigan JA, Roberts JAF. The blood groups in relation to peptic ulceration and carcinoma of the colon, rectum, breast and bronchus. BMJ. 1954;2(4883):315. [Free Full Text]
33.Clarke CA, Cowan WK, Edwards JW, et al. The relationship of ABO blood groups to duodenal and gastric ulceration. BMJ. 1955;2(4940):643. [Free Full Text]
34.Björkholm B, Lundin A, Sillen A, et al. Comparison of genetic divergence and fitness between two subclones of Helicobacter pylori. Infect Immun. 2001;69(12):7832–7838. [Abstract/Free Full Text]
35.Borén T, Falk P, Roth KA, et al. Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science. 1993;262(5141):1892. [Abstract/Free Full Text]
36.Aspholm-Hurtig M, Dailide G, Lahmann M, et al. Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin. Science. 2004;305(5683):519–522. [Abstract/Free Full Text]
37.Le Pendu J, Ruvoen-Clouet N, Kindberg E, Svensson L. Mendelian resistance to human norovirus infections. Semin Immunol. 2006;18(6):375–386.[CrossRef][Medline] [Order article via Infotrieve]
38.Thorven M, Grahn A, Hedlund K, et al. A homozygous nonsense mutation (428G-A) in the human secretor (FUT2) gene provides resistance to symptomatic norovirus (CGII) infections. J Virol. 2005;79(24):15351–15355. [Abstract/Free Full Text]
39.Larsson MM, Rydell GE, Grahn A, et al. Antibody prevalence and titre to norovirus (genogroup II) correlate with secretor (FUT2) but not with ABO phenotype or Lewis (FUT3) genotype. J Infect Dis. 2006;194(10):1422–1427.[CrossRef][Medline] [Order article via Infotrieve]
40.Shirato H, Ogawa S, Ito H, et al. Noroviruses distinguish between type 1 and type 2 histo-blood group antigens for binding. J Virol. 2008;82(21):10756–10767. [Abstract/Free Full Text]
41.Carlsson B, Kindberg E, Buesa J, et al. The G428A nonsense mutation in FUT 2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection. PloS One. 2009;4(5):e5593.[CrossRef][Medline] [Order article via Infotrieve]
42.Raza MW, Blackwell CC, Molyneaux P, et al. Association between secretor status and respiratory viral illness. BMJ. 1991;303(6806):815–818. [Abstract/Free Full Text]
43.Ali S, Niang MA, N'doye I, et al. Secretor polymorphism and human immunodeficiency virus infection in Senegalese women. J Infect Dis. 2000;181(2):737–739.[CrossRef][Medline] [Order article via Infotrieve]
44.Kindberg E, Hejdeman B, Bratt G, et al. A nonsense mutation (428G-A) in the fucosyltransferase FUT2 gene affects the progression of HIV-1 infection. AIDS. 2006;20(5):685–689.[Medline] [Order article via Infotrieve]
45.Blackwell CC, Jonsdottir K, Hanson MF, Weir DM. Non-secretion of ABO blood group antigens predisposing to infection by Haemophilus influenzae. Lancet. 1986;2(8508):687.[Medline] [Order article via Infotrieve]
46.Blackwell CC, Jonsdottir K, Hanson M, et al. Non-secretion of ABO antigens predisposing to infection by Neisseria meningitidis and Streptococcus pneumoniae. Lancet. 1986;2(8501):284–285.[CrossRef][Medline] [Order article via Infotrieve]
47.Sheinfeld J, Schaeffer AJ, Cordon-Cardo C, et al. Association of the Lewis blood-group phenotype with recurrent urinary tract infections in women. N Eng J Med. 1989;320(12):773–777.[Abstract]
48.Casals T, Vazquez C, Lazaro C, et al. Cystic fibrosis in the Basque country: high frequency of mutation delta F508 in patients of Basque origin. Am J Hum Genet. 1992;50(2):404–410.[Medline] [Order article via Infotrieve]
49.Taylor-Cousar JL, Zariwala MA, Burch LH, et al. Histo-blood group gene polymorphisms as potential genetic modifiers of infection and cystic fibrosis lung disease severity. PloS One. 2009;4(1):e4270.[CrossRef][Medline] [Order article via Infotrieve]
50.Roberts GF. Comparative Aspects of Haemolytic Disease of the Newborn. London: W. Heinemann; 1957.
51.Levine P, Stetson RE. An unusual case of intragroup agglutination. J Am Med Assoc. 1939;113:126. [Abstract/Free Full Text]
52.Mourant AE, Kope AC, Domaniewska-Sobczak K, The Distribution of the Human Blood Groups and Other Polymorphisms. 1976.
53.Kunierz-Alejska G, Bochenek S. Haemolytic disease of the newborn due to anti-Dia and incidence of the Dia antigen in Poland. Vox Sang. 1992;62(2):124–126.[Medline] [Order article via Infotrieve]
54.Zerjal T, Xue Y, Bertorelle G, et al. The genetic legacy of the Mongols. Am J Hum Genet. 2003;72(3):717–721.[CrossRef][Medline] [Order article via Infotrieve]
55.Mourant AE. The Distribution of the Human Blood Groups. Oxford, United Kingdom: Blackwell Scientific Publications; 1954.
56.Semino O, Passarino G, Oefner PJ, et al. The genetic legacy of Paleolithic Homo sapiens sapiens in extant Europeans: a Y chromosome perspective. Science. 2000;290(5494):1155–1159. [Abstract/Free Full Text]
57.Achilli A, Rengo C, Magri C, et al. The molecular dissection of mtDNA Haplogroup H confirms that the Franco-Cantabrian glacial refuge was a major source for the European gene pool. Am J Hum Genet. 2004;75(5):910–918.[CrossRef][Medline] [Order article via Infotrieve]
58.Gibbons A. Europeans trace ancestry to Paleolithic people. Science. 2000;290(5494):1080–1081. [Free Full Text]
59.Wells RS, Yuldasheva N, Ruzibakiev R, et al. The Eurasian heartland: a continental perspective on Y-chromosome diversity. Proc Natl Acad Sci U S A. 2001;98(18):10244–10249. [Abstract/Free Full Text]
60.Achilli A, Rengo C, Battaglia V, et al. Saami and Berbers—an unexpected mitochondrial DNA link. Am J Hum Genet. 2005;76(5):883–886.[CrossRef][Medline] [Order article via Infotrieve]
61.Colin Y, Cherif-Zahar B, Le Van Kim C, et al. Genetic basis of RhD-positive and Rh D-negative blood group polymorphism as determined by Southern analysis. Blood. 1991;78(10):2747–2752. [Abstract/Free Full Text]
62.Burton NM, Anstee DJ. Structure, function and significance of Rh proteins in red cells. Curr Opin Hematol. 2008;15(6):625–630.[CrossRef][Medline] [Order article via Infotrieve]
63.Busquets J, Castellote J, Torras J, et al. Liver transplantation across Rh blood group barriers increases the risk of biliary complications. J Gastrointest Surg. 2007;11(4):458–463.[CrossRef][Medline] [Order article via Infotrieve]
64.Chérif-Zahar B, Bloy C, Le Van Kim C, et al. Molecular cloning and protein structure of a human blood group Rh polypeptide. Proc Natl Acad Sci U S A. 1990;87(16):6243–6247. [Abstract/Free Full Text]
65.Hanvesakul R, Spencer N, Cook M, et al. Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation. Am J Transplant. 2008;8(9):1931–1941.[CrossRef][Medline] [Order article via Infotrieve]
66.Parham P. Immunogenetics of killer cell immunoglobulin-like receptors. Mol Immunol. 2005;42(4):459–462.[CrossRef][Medline] [Order article via Infotrieve]
67.Parham P. MHC class I molecules and KIRS in human history, health and survival. Nat Rev Immunol. 2005;5(3):201–213.[CrossRef][Medline] [Order article via Infotrieve]
68.Santin I, de Nanclares GP, Calvo B, et al. Killer cell immunoglobulin-like receptor (KIR) genes in the Basque population: association study of KIR gene contents with type 1 diabetes mellitus. Hum Immunol. 2006;67(1–2):118–124.[CrossRef][Medline] [Order article via Infotrieve]
69.Flegr J, Klose J, Novotna M, et al. Increased incidence of traffic accidents in Toxoplasma-infected military drivers and protective effect RhD molecule revealed by a large-scale prospective cohort study. BMC Infect Dis. 2009;9:72.[CrossRef][Medline] [Order article via Infotrieve]
70.Singleton BK, Green CA, Avent ND, et al. The presence of an RHD pseudogene containing a 37-base pair duplication and nonsense mutation in Africans with the RhD-negative blood group phenotype. Blood. 2000;95(1):12–18. [Abstract/Free Full Text]
71.Touinssi M, Chapel-Fernandes S, Granier T, et al. Molecular analysis of inactive and active RHD alleles in native Congolese cohorts. Transfusion. 2009;49(7):1353–1360.[CrossRef][Medline] [Order article via Infotrieve]
72.Weatherall DJ. Genetic variation and susceptibility to infection: the red cell and malaria. Br J Haematol. 2008;141(3):276–286.[Medline] [Order article via Infotrieve]
73.Penman BS, Pybus OG, Weatherall DJ, et al. Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean. Proc Natl Acad Sci U S A. 2009;106(50):21242–21246. [Abstract/Free Full Text]
74.Nagel RL, Steinberg MH. Genetics of the beta S gene: origins, epidemiology, and epistasis. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge, MA: Cambridge University Press; 2001:711–755.
75.Chotivanich K, Udomsangpetch R, Pattanapanyasat K, et al. Hemoglobin E: a balanced polymorphism protective against high parasitemias and this severe P falciparum malaria. Blood. 2002;100(4):1172–1176. [Abstract/Free Full Text]
76.Kun JF, Mordmuller B, Lell B, et al. Polymorphism in promoter region of inducible nitric oxide synthase gene and protection against malaria. Lancet. 1998;351(9098):265–266.[CrossRef][Medline] [Order article via Infotrieve]
77.Miller LH, Mason SJ, Clyde DF, et al. The resistance factor to Plasmodium vivax in blacks: the Duffy blood group genotype FyFy. N Engl J Med. 1976;295(6):302–304.[Abstract]
78.Tournamille C, Colin Y, Cartron JP, et al. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy negative individuals. Nat Genet. 1995;10(2):224–228.[CrossRef][Medline] [Order article via Infotrieve]
79.Zimmerman PA, Woolley I, Masinde GL, et al. Emergence of FY*A(null) in a Plasmodium vivax endemic region of Papua New Guinea. Proc Natl Acad Sci U S A. 1999;96(24):13973–13977. [Abstract/Free Full Text]
80.Olsson ML, Smythe JS, Hansson C, et al. The Fyx phenotype is associated with a missense mutation in the Fyb allele predicting Ar89Cys in the Duffy glycoprotein. Br J Haematol. 1998;103(4):1184–1191.[CrossRef][Medline] [Order article via Infotrieve]
81.Ryan JR, Stoute JA, Amon J, et al. Evidence for transmission of Plasmodium vivax among a Duffy antigen negative population in western Kenya. Am J Trop Med Hyg. 2006;75(4):575–581. [Abstract/Free Full Text]
82.Cavasini CE, Mattos LC, Couto AA, et al. Plasmodium vivax infection among Duffy antigen negative individuals from the Brazilian Amazon region: an exception? Trans R Soc Trop Med Hyg. 2007;101(10):1042–1044.[CrossRef][Medline] [Order article via Infotrieve]
83.Hadley TJ, Lu Z, Wasniowska K, et al. Postcapillary venule endothelial cells in kidney express a multispecific chemokine receptor that is structurally and functionally identical to the erythroid isoform, which is the Duffy blood group antigen. J Clin Invest. 1994;94(3):985–991.[Medline] [Order article via Infotrieve]
84.Gardner L, Patterson AM, Ashton BA, et al. The human Duffy antigen binds selected inflammatory but not homeostatic chemokines. Biochem Biophys Res Commun. 2004;321(2):306–312.[CrossRef][Medline] [Order article via Infotrieve]
85.Pruenster M, Mudde L, Bombosi P, et al. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nat Immunol. 2009;10(1):101–108.[CrossRef][Medline] [Order article via Infotrieve]
86.Segerer S, Regele H, Mack M, et al. The Duffy antigen receptor for chemokines is
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References
The relative contribution of founder effects and natural selection to the observed distribution of human blood groups has been debated since blood group frequencies were shown to differ between populations almost a century ago. Advances in our understanding of the migration patterns of early humans from Africa to populate the rest of the world obtained through the use of Y chromosome and mtDNA markers do much to inform this debate. There are clear examples of protection against infectious diseases from inheritance of polymorphisms in genes encoding and regulating the expression of ABH and Lewis antigens in bodily secretions particularly in respect of Helicobacter pylori, norovirus, and cholera infections. However, available evidence suggests surviving malaria is the most significant selective force affecting the expression of blood groups. Red cells lacking or having altered forms of blood group-active molecules are commonly found in regions of the world in which malaria is endemic, notably the Fy(a–b–) phenotype and the S-s– phenotype in Africa and the Ge– and SAO phenotypes in South East Asia. Founder effects provide a more convincing explanation for the distribution of the D– phenotype and the occurrence of hemolytic disease of the fetus and newborn in Europe and Central Asia.
Introduction
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References
Hirszfeld and Hirszfeld1 showed the frequencies of blood groups A and B differ between populations. Their observations raised fundamental questions regarding the causes of these differences, which were eloquently summarized by Mourant et al2(p1):
Were the differences the result of random genetic drift and founder effects, in small populations which later multiplied and stabilized the original, fortuitous, frequencies, or were they the result of natural selection, arising from differences in fitness between the various blood groups, fitnesses which themselves depended upon locally determined features of the external environment?
Mourant et al concluded that "most workers now agree that both processes are operative, but their relative importance remains in question."2
We now have detailed information concerning almost all the genes giving rise to blood group polymorphisms, the structure of the gene products and the antigens themselves, and in many cases functional information sufficient to delineate mechanisms of interaction with external agents.3–5 In addition, studies on the tracking of Y chromosome and mtDNA haplotypes in human populations provide us with unprecedented information concerning the significance of genetic drift and founder effects in determining the genetic background of different world populations.6 Given this new information, it seems an appropriate time to revisit these questions and ask whether we are any nearer understanding the relative importance of natural selection and founder effects in determining the distribution of human blood groups.
Infectious diseases and selection for ABO blood group antigens
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References
The molecular basis of the ABO blood group system was elucidated in 1990.7 The gene encodes a glycosyltransferase, which transfers N-acetyl D-galactosamine (group A) or D-galactose (group B) to the nonreducing ends of glycans on glycoproteins and glycolipids. The group O phenotype results from inactivation of the A1 glycosyltransferase gene, and the nonreducing ends of the corresponding glycans in group O subjects express the blood group H antigen (Figure 1A). The ABH antigens are not confined to red cells but are widely expressed in body fluids and tissues. The biologic significance of the A/B transferase has not been clearly demonstrated, but it would be expected that loss of this functional protein in group O patients would have some deleterious consequences for patients of this blood type.
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Figure 1. Structure of ABO, H, and Lewis antigens. (A) Structure of ABO and H antigens on human red cells. H antigen formed by the action of FUT1 on oligosaccharide precursor chains in which the terminal D-galactose residue is linked to carbon 4 of the penultimate N-acetyl D-glucosamine residue (type II chain). (B) Structure of Le blood group antigens in bodily secretions. Secretor gene (FUT2) regulates the production of H antigen, which can be converted to A or B antigen if the corresponding active ABO glycosyltransferase is present. The ABH, Leb-active structures are formed on oligosaccharide precursor chains in which the terminal D-galactose residue is linked to carbon 3 of the penultimate N-acetyl D-glucosamine residue (type I chain) If FUT 2 is deficient the Lea active structure predominates.
One of the most significant disease associations described for non-O (subjects of group A, B, or AB) versus O subjects is susceptibility to arterial and venous thromboembolism (VTE).8,9 Non–group O patients have a greater risk of VTE than patients of group O and have greater levels of von Willebrand factor (vWF) and factor VIII.8,10 The risk of VTE is probably related to the level of vWF and factor VIII because patients of group A2 have lower levels of these proteins than A1, B, and AB and have a lower risk of VTE.9 A, B, and H blood group antigens are expressed on N-glycans of vWF and influence the half-life of the protein (10 hours for group O and 25 hours for non-O subjects), providing an explanation for the greater levels in non-O patients.11 These observations raise the possibility that a greater propensity for blood clot formation in non-O patients conferred a survival advantage to early humans. Such an argument has been made for the occurrence of the prothrombotic mutations factor V Leiden and prothrombin 20210G>A, which are commonly found in white humans dated as occurring 20 000 to 24 000 years ago toward the end of the last ice age.12 It is proposed that mutations like factor V Leiden lower the risk of hemorrhage and/or severe infections and thereby the risk of death during pregnancy.13 A similar hypothesis could explain the function of A and B antigens on vWF.
What then was the stimulus that caused the inactivation of this gene and the creation of the group O phenotype, which is so prevalent throughout the world? Evidence supporting the view that blood group O provides a selective advantage against severe malaria has been recently reviewed.14–16 The argument is persuasive. Group O is presumed to have arisen in Africa before the migration of early humans. Severe malaria results in the death of millions each year before they reach child-bearing age, and therefore selects survival genes.17 Experimental support for the hypothesis is provided by Fry et al18 and by Rowe et al.19 Rowe et al19 report reduced rosetting of Plasmodium falciparum isolates from group O Malian children compared with non-O blood groups. Parasitized red cells form rosettes with uninfected red cells and adhere to vascular endothelium, causing vasocclusion and severe disease.
There are other examples of infectious diseases in which the severity of infection can be directly linked to ABO phenotype. The authors of numerous studies have shown that once a person is infected with cholera (Vibrio cholerae strains O1 El Tor and O139) the phenotype group O confers a greater likelihood of severe infections than non-O blood group phenotypes.20 Glass et al21 suggest that the low prevalence of group O and high prevalence of group B in the Ganges Delta in Bangladesh is directly related to selective pressure from cholera. Almost all recent cholera pandemics have emanated from this region of the world.22 Patients of group O were more susceptible in an outbreak of gastrointestinal infections caused by Escherichia coli O157 in Scotland in 1996. A total of 87.5% of patients who died were group O.23
However, suggestions that smallpox selects against A, thereby explaining the high frequency of group A in Europe, and that the low frequency of O in ancient plague centers in Mongolia and the Middle East is also a reflection of selection are not supported by adequate data (Vogel et al [1960], cited in Mourant et al2(p18); Kreiger and Morton24). More recent studies have linked the high frequency of the HIV-1 resistance mutation CCR532 in Europe with protection against smallpox and the Black Death.25 This proposal has also been questioned.26 The mutations AO and CCR32 occurred much earlier in human evolution than the plague and smallpox epidemics of medieval times. As discussed previously, the AO mutation was likely driven by malaria in Africa before the migration of early humans to Europe, and CCR 32 has been described in skeletons from the Bronze Age.25 A combination of selection against infectious diseases, such as plague and smallpox, and genetic drift and founder effects in small populations (resulting from migration patterns of early humans) may ultimately explain the allele frequencies observed today.
The expression of ABH antigens in tissues and body fluids other than blood cells is regulated by the secretor gene (FUT2), which encodes an alpha 1,2-fucosyltransferase capable of transferring L-fucose to carbon 2 of galactose (beta, 1-3) N-acetyl D-glucosamine–containing glycans. In the absence of an active FUT2 gene (nonsecretor), the structure created is the Lea antigen.27 The product of the Le gene is an alpha 1,3/4 fucosyltransferase (FUT3), which transfers L-fucose to carbon 4 of the penultimate N-acetyl-D-glucosamine residue of the same glycans.28 The structure created in tissues by the combined action of FUT2 and FUT3 is the Leb antigen. A and B antigens can only be formed in the tissues of patients with an active FUT2 by the action of alpha-glycosyltransferases capable of transferring N-acetyl D-galactosamine or D-galactose to carbon 3 of the same glycans (Figure 1B). The secretions and tissues of a person with an active FUT2 (a secretor) can express A, B, H, and Leb antigens in those secretions according to the glycosyltransferase genes inherited. In European and African nonsecretors, the homozygous inheritance of a nonsense mutation (G428A) inactivating FUT2 denoted se428 is frequently found (20% of Europeans).29 In the Far East and Pacific regions, the commonest mutation in FUT2 (A385T, se385) causes a single amino acid change (Ile129Phe) in the stem region of the fucosyltransferase, resulting in a 5-fold reduction in active enzyme and a weak Le(a+b+) phenotype.30 Sequencing FUT2 in 732 patients from 39 populations confirmed the widespread occurrence of the se428 allele in Europe, Central Asia, and Africa and the se385 allele in the Far East and Pacific and mapped 2 further se alleles with a more restricted distribution (se302 and se571) to Central and South Asia and Cambodia, respectively.31 Possession of homozygosity for a nonsecretor phenotype has a demonstrable survival advantage for some infectious diseases.
One of the first proven associations of a blood group polymorphism with disease was that between group O and peptic ulceration.32,33 The gastric pathogen H pylori is now known to be a causative agent leading to peptic ulceration and gastric cancer. According to Björkholm et al,34 H pylori has established colonies in the stomachs of approximately one-half the world's population.34 Early studies demonstrated that a South American strain of H pylori P466 bound to blood group O Leb but not ALeb structures on the gastric epithelium, thereby providing a clear explanation for the greater susceptibility of group O secretors.35 More recent studies on strains of H pylori from different parts of the world have shown that not all strains are so specific for O Leb, with many strains from outside South America having binding capabilities for ALeb in addition to OLeb. Nevertheless, these strains have a greater binding affinity for OLeb compared with ALeb (approximately 5-fold [median] greater).36 Sequence analysis of the bacterial surface molecule responsible for binding to gastric epithelium BabA (blood group antigen binding adhesin) from different strains of H pylori showed that Peruvian strains were closely related to Spanish but not to Asian strains, raising the intriguing possibility that the OLeb-specific strains found in South American may have arisen after European colonization of South America in the 16th century and represent adaptation to a population that is almost entirely of the blood group O phenotype.36
Susceptibility to norovirus infection is also closely linked to the expression of ABH and Le antigens in the gastrointestinal tract. Noroviruses are the commonest cause of acute gastroenteritis in humans and are estimated to account for 60% to 85% of all gastroenteritis outbreaks in developing countries.37 They are transmitted by consumption of contaminated food, particularly oysters, which appear able to concentrate the virus, or exposure to contaminated water.37 The pivotal role of secretor status in determining susceptibility to norovirus has been clearly demonstrated by Thorven et al,38 who compared susceptibility to gastroenteritis in patients and medical staff involved in hospital outbreaks in Sweden. The results demonstrated that only those patients homozygous for nonsecretor were protected from infection. Larsson et al39 further demonstrated significantly lower antibody titers to norovirus GGII in nonsecretors compared with secretors. There are many different strains of norovirus, however, and some strains bind to nonsecretor Lea structures and cause symptomatic infection.40,41The variable specificity of different strains for ABH and Leb structures reported reflects a similar diversity to that of the aforementioned H pylori. Evidence for greater susceptibility of secretors to influenza viruses, rhinoviruses, respiratory syncytial virus, and echoviruses has also been presented.42 Reduced risk of HIV type 1 infection was found in Senegalese commercial sex workers with the nonsecretor type.43 Slow disease progression of HIV-1 in nonsecretors was also reported by Kindberg et al.44
Nonsecretors appear more susceptible to infections by Haemophilus influenzae,45 Neisseria meningitidis, and Streptococcus pneumoniae46 and urinary tract infection caused by E coli.47
A mutation (F508) in the cystic fibrosis transmembrane regulator gene (CFTR) is common in European patients and was present in Europe during the Paleolithic period more than 10 000 years ago.48The possibility that differences in A, B, and H antigen expression in the airway mucus might lead to differences in microbial binding and predispose to more severe lung disease was investigated in 808 patients homozygous for F508. No association with ABO, Se, or Le genotype was observed.49
Rh blood groups and the origin of hemolytic disease of the fetus and newborn
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
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References
The major clinical disease associated with the Rh blood group system is hemolytic disease of the fetus and newborn (HDFN). HDFN usually arises when a mother who is blood group D– carries a fetus who is blood group D+, and fetal red cells released into the maternal circulation immunize the mother to make antibody to D, which traverses the placenta and damages the fetus. Before the introduction of a successful prophylactic treatment in 1968, the frequency of the disease in England and North America was approximately 1 per 170 births.3 Recognition of the disease as a single entity was slow to emerge. In severe cases anti-D crosses the placenta and causes death of the fetus in utero, a condition known as hydrops fetalis. More commonly, disease occurs in the neonatal period, where severe and acute anemia and severe jaundice is fatal, a condition known as icterus gravis neonatorum. Roberts50 cites an account of Louyse Bourgeois, a midwife of Marie de Medici, who published in 1609 what is probably the earliest account of hydrops fetalis in one twin and neonatal jaundice in the other and credits Auden (1905) with several key observations relating to neonatal jaundice, in particular its appearance in successive children of the same parents. The recognition that hydrops fetalis and neonatal jaundice were manifestations of the same disease gradually emerged during the 1920s, and anti-D was shown to be the causative agent in 1939.51
There is now a formidable body of evidence to support the hypothesis that humans originated in Africa and to inform the timescale of various migrations from Africa, which have led to the world populations we have today.6 Simply by overlaying the known distribution of blood group frequencies on the world map of human migrations, the potential significance of genetic drift and founder effects is apparent. Wells6 argues, for example, that it is possible to account for all of the mtDNA and Y-chromosome types in Native Americans with a founding population of 10 to 20 people. Little wonder then that Native Americans are almost exclusively blood group O52 or that the Dia blood group polymorphism tracks the migration of humans from East Asia to the Americas.52 The occurrence of the Dia antigen in South East Poland also provides a measure of the extent to which the Mongol invasions penetrated Europe in more recent times.53,54
In Europe a similar founder effect can be invoked to explain the high frequency of the D– phenotype. The emergence of Paleolithic ancestors surviving the last ice age from refuges in the Basque region of Northern Spain and Southern France and the Ukraine 10 000 to 15 000 years ago and subsequent interbreeding of these survivors with Neolithic migrants from the Middle East provides an explanation for the occurrence of HDFN. To explain the high frequency of the D– allele in Europe, Mourant55 proposed a mixing of 2 populations, one essentially D– and the other D+. He noted that D– frequency was very high in the Basques and postulated the mixing of Paleolithic peoples from the Basque region with Neolithic migrants as the cause. This hypothesis has been largely ignored in the succeeding years, but recent observations made with the use of mtDNA and Y-chromosome markers have led to wide acceptance of the population-mixing hypothesis (Figure 2).52,56–58
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Figure 2. Paleolithic settlers from the last glacial maximum may be the source of the high frequency of D– allele in Europeans. (Top) European location of Paleolithic refuges at the time of the last glacial maximum. Note migration of population containing marker M173 (from Gibbons58; reprinted with permission from American Association for the Advancement of Science). (Bottom) Distribution of the D– allele in Europe (from Mourant et al52; reprinted by permission of Oxford University Press).
Tracking of haplotypes emerging from the Basque and Ukrainian refuges has shown that these populations migrated throughout Europe and Central Asia and into India and Pakistan.59 HDFN is found in all these regions. Mourant55 also suggested a link between the Basques and the Berbers of North Africa because of the high frequency of D– phenotypes among Berbers. This hypothesis is now supported by evidence from maternal DNA markers showing that ancestral Berbers occupied the Basque refuge area and migrated back into North Africa.60 In Western Europe, the D– phenotype results from a complete deletion of RHD.61 The molecular basis of D– phenotype has not been formally determined for Ukrainian D– people. Loss of RhD protein does not appear to be of significant detriment to red cell function. The best available structural models for RhD protein and its homologue RhCE protein indicate they do not function as transport proteins but rather serve to facilitate the assembly of the band 3 protein gas transport complex in the red cell membrane. These observations suggest there is considerable functional redundancy, with D and CE proteins effectively substituting for each other (Figure 3).62
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Figure 3. Structure of the human red cell membrane showing the major surface proteins and minor proteins Fy and CR1. Two major membrane complexes linked to the underlying red cell skeleton are depicted. The Band 3 complex containing glycophorins A (GPA) and B (GPB) and Rh proteins, Rh-associated protein (RhAG), CD47, LW glycoprotein (intercellular adhesion molecule–4), and the junctional complex comprising glycophorins C and D (GPC, GPD), Kell glycoprotein, XK glycoprotein, and Duffy (Fy) glycoprotein. Aquaporin 1 (AQP1), the glucose transporter (GLUT1), decay accelerating factor (DAF, CD55), and complement receptor 1 (CR1) are also shown. ABH active oligosaccharides known to be present on all major surface proteins except Rh proteins are not depicted.
A counterargument to the population mixing hypothesis would be provided by a clear demonstration of selection for D– phenotype by environmental factors. In a thorough review of early studies seeking to identify associations between the D polymorphism and diseases, Mourant et al2 revealed no convincing associations. More recently, 2 studies have reported an association of the D polymorphism with disease. Busquets et al,63 in a study from Barcelona, reported an increased incidence of biliary complications in transplant recipients of livers mismatched for D. The presence of biliary complications in D-nonidentical graft-host cases (23 [30%] of 76) was greater than in D-identical grafts (47 [17%] of 269). Rh polypeptides are not expressed in liver,64 and therefore the mechanism of such an association is not clear. The fact that the study took place in the Basque region of Spain, where the D– phenotype is very common and may result from ancestral Paleolithic settlements, may be very relevant to the interpretation of these findings because it raises the possibility that other genes more relevant to transplantation and also occurring more commonly in Basques than in other populations may be influencing the results. In this context it is interesting to note evidence that donor human leukocyte antigen C (HLA-C) genotype has a profound impact on the outcome of liver transplants.65 HLA-C is the major inhibitory ligand for killer cell immunoglobulin-like receptors (KIRs). KIR genes are highly polymorphic and are expressed on natural killer cells and a subset of T lymphocytes.66,67 Several KIR genes (KIR2DS5, KIR3DS1, KIR2DL2) are significantly different in frequency in Basques, and 3 novel haplotypes were identified by Santin et al.68
Flegr et al69 in a study from the Czech Republic report an association of the polymorphism with Toxoplasma gondii infection whereby subjects (military conscripts) with the D– phenotype who were infected with T gondii (11 [6.08%] of 181) had slower reaction times and consequently were involved in more road traffic accidents than D+ patients infected with T gondii (17 [2.4%] of 709). Rh D protein is not reported to be expressed in brain; therefore, the likely mechanism of such an association is obscure, and given the small numbers of T gondii-infected patients involved in the study, a much larger cohort study will be required to prove the validity of this association.
Considering the evidence thus far, it appears most likely that the frequency of D+ and D– negative phenotypes in Europe and Central Asia is a reflection of genetic drift and migration rather than natural selection, with the early colonists of Europe emerging from Africa with a deletion of RHD (Figure 2). There remains the possibility the original stimulus driving this deletion occurred in Africa as a result of selection. The concomitant occurrence of the D– phenotype in African populations resulting from a different molecular mechanism70,71 may be suggestive of some ancient selective pressure.
Malaria: evidence for selection of blood group phenotypes that are rare outside areas in which malaria is endemic
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Abstract
Introduction
Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
Authorship
References
It appears likely that the most devastating effects of malaria on human populations coincided with a change of lifestyle from hunter gatherer to more sedentary agricultural practices circa 10 000 years ago.15 The clearance of trees from forest areas created the potential for pools of stagnant water and breeding grounds for the mosquitoes carrying parasites.
The clearest examples of selection in the face of malaria are reflected in the widespread distribution of inherited anemias, particularly sickle cell anemia and alpha thalassemia and the occurrence of hemoglobin C in regions of the world where malaria is endemic.72,73 The mutation giving rise to sickle cell disease (SCD; HbS) may have arisen at 3 different sites in Africa (Atlantic West Africa, Central West Africa, and Bantu-speaking Central and Southern Africa) with expansion of the mutation occurring 2000 to 2500 years ago.74 In this case, patients who inherit an HbS gene from both parents have SCD, whereas those who are heterozygous inheriting the HbS gene from 1 parent and the normal HbA gene from the other parent have substantial protection against malaria. A similar protective effect for the heterozygote seems likely in South East Asia, where HbE is very common and red cells from patients of genotype HbAE are markedly less susceptible to malaria parasite invasion in vitro.75
Further illustrations of the diversity of mutations that have arisen in response to malaria are deficiency of glucose-6 phosphate dehydrogenase, which is widespread in Mediterranean and India,72 and a polymorphism in the promoter of inducible nitric oxide synthase.76
Plasmodium vivax and the blood group Fy(a–b–) phenotype
Complete absence from red cells of the molecule carrying the Duffy blood group antigens (aka DARC) is found in almost 100% of West Africans, and this absence is clearly and unambiguously demonstrated to provide protection from P vivax.77 The molecular basis of this Duffy deficiency is a point mutation in the binding site for the transcription factor GATA-1.78 GATA-1 is a DNA-binding protein essential for erythropoiesis, and its failure to bind to the Duffy gene promoter means that the Duffy protein is absent from the red cells of affected subjects. In Africans the mutation occurs on a Duffy allele that would otherwise generate a Fy(b+) phenotype. The same GATA-1 mutation appears to have occurred on a second occasion in South East Asia, where it occurs on a Duffy allele that would otherwise generate a Fy(a+) phenotype.79 Another mutation creating weak expression of Duffy (Fyx) may also be relevant to malaria, but relevant population studies have not been reported.80 Recently, evidence for the emergence of P vivax strains capable of invading Fy(a–b–) red cells has emerged in South America and East Africa.81,82
The protective effect of the Fy(a–b–) phenotype against P vivax is clear and unambiguously established. Not so clear are any deleterious consequences of this mutation for the subjects expressing the phenotype. Duffy protein is expressed on endothelial cells in these subjects but not on red cells,83 so any attempt to understand the consequences of red cell Duffy deficiency must take account of the functional role of endothelial Duffy. The Duffy protein is a member of the 7 membrane-spanning chemokine receptor family (Figure 3) but unlike most chemokine receptors does not effect intracellular signaling through G proteins. It binds several proinflammatory chemokines of both the CXC and CC subfamilies but does not bind homeostatic chemokines.84 Recent evidence suggests Duffy protein on endothelial cells binds chemokines and facilitates leukocyte extravasation contributing to disease pathogenesis through inflammation.85 Evidence for up-regulation of Duffy expression in the vascular endothelium during infection and transplant rejection supports this view.86,87
The lack of Duffy on red cells in Fy(a–b–) patients alters the balance of proinflammatory chemokines in the body because the very large capacity of red cell binding is absent but the consequences of this change are presently unclear. Lee et al88 provide evidence that red cell and endothelial Duffy regulate the kinetics of chemokine bioavailability between the circulation and extravascular sites during inflammation. Clearly this regulation would be altered in Fy(a–b–) subjects. In a mouse model, inflammation induced by polycytidylic acid significantly enhanced alloimmunization to red cells.89 In this context it is interesting to note that patients with SCD are predominantly of the Fy(a–b–) phenotype and that the production of multiple red cell alloantibodies upon transfusion (usually with blood from white donors) is a frequent and significant problem encountered by employees of blood banks seeking to provide compatible blood for the patients (reviewed in Anstee90). SCD patients in sickle cell crisis and mouse models of human SCD have many indicators of an inflammatory response.91 These data suggest that the enhanced propensity for alloimmunization in SCD patients is related to inflammation and also pose the question as to the significance of Fy(a–b–) in this process. Are Fy(a–b–) SCD patients more likely to make alloantibodies in response to transfusion than SCD patients of normal Fy phenotype? Is there a link between regulation of proinflammatory chemokine availability by red cell Fy and the adaptive immune response?
The data of Afenyi-Annan et al92 provide evidence that SCD patients with the Fy(a–b–) phenotype are more susceptible to chronic organ damage and proteinuria than SCD patients of normal Fy phenotype and are consistent with such an hypothesis. Interpretation is likely also influenced by genetic differences of immune response and cytokine genes in African populations compared with other world populations,93,94 but the genetic backgrounds of SCD patients with normal and Fy(a–b–) phenotype may be sufficiently comparable to allow conclusions regarding alloimmunization and the role of Fy to be drawn. Should Fy(a–b–) subjects be more susceptible to alloimmunization, then the potential use anti-inflammatory therapies in the treatment of vaso-occlusion95,96 may have the added bonus of reducing rates of red cell alloimmunization and provide a much needed alternative approach to a major transfusion problem.
A further consequence of selection for the Fy(a–b–) phenotype in Africa may be to alter the kinetics of HIV-1 infection in those with this phenotype. Several HIV-1 strains bind to Duffy on normal red cells, facilitating the transfer of HIV-1 to its target cells (CD4+/CCR5+ T lymphocytes) with 5- to 12-fold greater efficiency than Fy(a–b–) red cells.97 He et al97 calculate that patients with the Fy(a–b–) phenotype have a 40% greater likelihood of acquiring HIV than those lacking the phenotype; however, the disease, once acquired, has a slower progression than in infected patients of normal Fy type. They conclude that these differences are related to loss of competition for binding HIV-1 between plasma chemokine CCR5 and Duffy on red cells in Fy(a–b–) subjects and consequent changes in the inflammatory state those infected. The findings of this study have been contested by Walley et al,98 who used different methodology to analyze a different cohort of HIV+ and HIV– African American subjects and found no association between Fy genotype and progression to AIDS or risk for HIV acquisition. They also point out that the number of HIV– patents used by Walley et al98 was much smaller (227 vs 814) and suggest this difference may be a major factor affecting the analysis.99
Different strains of P falciparum use different blood group proteins as receptors
The dual availability of in vitro culture systems to study the invasion of human red cells by P falciparum and well-characterized rare blood group phenotypes made it possible to identify red cell receptors used by different parasite strains. Early studies on cells lacking Glycophorin A (Ena– cells100) and glycophorin B (S-s– cells101) provided evidence that these sialic acid–rich red cell-surface glycoproteins were parasite receptors and these observations have been confirmed.102–105 Glycophorins C (GPC) and D (Ge– red cells) are also receptors for some strains of P falciparum.106–108 Glycophorins are major proteins at the red cell surface (Figure 3). Glycophorin A (GPA) and the major anion transport protein (AE1, Band 3) with approximately 106 copies/red cell are the most abundant red cell surface proteins with glycophorins B, C, and D together accounting for a further 450 000 copies per red cell.109,110
Perhaps surprisingly, there is little experimental evidence to suggest selection against the expression of GPA has occurred in response to P falciparum infection. Red cells from patients having the hybrid GPA-GPB protein Dantu, which is common in certain parts of Africa, are reported to resist invasion,111 and it has been suggested that elevated expression of Band 3 occurring in patients with the GPB-GPA-GPB MiIII protein common in South East Asia may be relevant to malaria survival.112 The importance of sialic acid on GPA in forming a receptor for P falciparum102 suggests that red cells expressing glycosylation variants of GPA found commonly in Africans in which N-acetyl D-glucosamine is present in some of the sialic acid–rich O-glycans at the N-terminus (patients with the M1 antigen113) may be relevant to one's susceptibility to malaria.
In contrast to the situation with GPA, subjects lacking glycophorin B are found in high frequency in central Africa.105 Patients with red cells lacking GPC and glycophorin D (Ge–, Leach phenotype) are very rare, but those with Ge– red cells having an altered GPC resulting from deletion of exon 3 of GYPC114,115 are common in Melanesians, most notably in Papua New Guinea, and the resulting phenotype provides protection against P falciparum (Figure 4).72,108 Clearly, different strains of P falciparum target glycophorins associated with one or other of the membrane complexes, providing key cytoskeletal linkages maintaining the stability of the red cell membrane (Figure 3) and selection, resulting in loss or alteration of glycophorins in either of these sites confers a survival advantage.
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Figure 4. Distribution of rare blood group phenotypes selected by malaria in Africa and South East Asia. The location of rare blood group phenotypes lacking glycophorin B (S-s–), having altered glycophorin C (Ge–; Gerbich-negative), Fy (Duffy) blood group–null allele (Fy), Sl(a–) allele of complement receptor 1 (CR1), and the Band 3 mutation causing South East Asian ovalocytosis (SAO) in comparison with the distribution of HbS and HbE alleles.72
Melanesians also exhibit another example of selection, affording protection against cerebral malaria, a phenotype known as South East Asian ovalocytosis. South East Asian ovalocytosis cells, as the name implies, have an abnormal shape. They are also characterized by weakened expression of a large number of blood group antigens, including antigens found on Band 3, GPA, and the Rh blood group proteins.116 In this case selection favors the heterozygote. Heterozygotes inherit a normal Band 3 gene together with a mutant inactive Band 3 gene resulting from a deletion, causing a loss of 9 amino acids at the point at which the cytoplasmic N-terminal domain enters the cytosolic face of the lipid bilayer (reviewed in Bruce117). Homozygous inheritance of this mutation would result in total Band 3 deficiency. Because Band 3 is essential for respiration (Cl/HCO3 exchange) and for maintaining the integrity of the red cell membrane, it must be assumed in evolutionary terms that such an inheritance is incompatible with survival. Rare subjects with total Band 3 deficiency states have been described, but survival depends on extensive medical support, particularly in the neonatal period.118
Complement receptor 1 (CR1; Figure 3) carries antigens of the Knops blood group system. CR1 expression is very variable between patients and red cells expressing fewer than 100 copies CR1 per cell show reduced rosetting with P falciparum strain R29R, as do red cells expressing the Sla– blood group phenotype. The Sla– phenotype, which results from a single nucleotide polymorphism (R1601G) in long homologous repeat D, occurs in only 1% of the white population but reaches 70% in Malians.119–121
Conclusions
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Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
Conclusions
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References
The significance of human blood groups can now be seen more clearly in the context of population movement, and the constant battle between humans and infectious disease. Evidence for selection by infectious diseases at the level of the ABO and secretor genes is persuasive but for other blood group antigens, founder effects appear more likely to account for the distribution of blood group polymorphisms except that is, in parts of the world in which malaria is endemic. Available data suggest survival from malaria has been the most significant selective force acting on the blood groups.
Rare blood group phenotypes revealed through compatibility testing in transfusion centers and blood banks throughout the world have provided powerful tools with which to investigate the mechanisms whereby malarial parasites invade human red cells. However, a comprehensive study of the distribution of known blood group polymorphisms in areas in which malaria is endemic has not been undertaken. Now that almost all the blood group genes have been cloned and the molecular bases of most antigens determined, it is feasible to conduct such a study with the use of high-throughput DNA-based methods.122–125 Furthermore, the availability of rapid DNA sequencing methodologies presages an era in which mass screening of genes encoding red cell membrane proteins could be used to identify new polymorphisms of relevance to malarial invasion. Studies of this type, focused in tropical Africa, South East Asia, and Latin America, would provide a valuable database of new information about blood group diversity in populations inhabiting these regions not only for malarial epidemiologists but also for those investigating human susceptibility to new emerging infectious diseases given that zoonoses from wildlife in these regions have been identified as the most significant growing threat to global health of all emerging infectious diseases.126
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Malaria: evidence for selection...
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Contribution: D.J.A. wrote the manuscript.
Conflict-of-interest disclosure: The author declares no competing financial interests.
Correspondence: David Anstee, Bristol Institute for Transfusion Sciences, NHS Blood and Transplant, Bristol, BS34 7QG United Kingdom; e-mail: david.anstee@nhsbt.nhs.uk .
Acknowledgments
The author thanks Lesley Bruce of the Bristol Institute for Transfusion Science for preparing Figure 3, David Briggs of NHS Blood and Transplant for helpful discussions regarding HLA-C and KIR receptors, and Geoff Daniels of the Bristol Institute for Transfusion Science for critical reading of the manuscript.
The author's work is supported by Department of Health (England).
Footnotes
Submitted January 21, 2010; accepted February 18, 2010.
Prepublished online as Blood First Edition Paper, March 22, 2010 DOI: 10.1182/blood-2010-01-261859
References
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Infectious diseases and...
Rh blood groups and...
Malaria: evidence for selection...
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References
1.Hirszfeld L, Hirszfeld H. Serological differences between the blood of different races. Lancet. 1919;197:675–679.
2.Mourant AE, Kope AC, Domaniewska-Sobczak K. Blood Groups and Diseases. Oxford, United Kingdom: Oxford University Press; 1978.
3.Klein HG, Anstee DJ, eds. Mollison's Blood Transfusion in Clinical Medicine (11th ed). Oxford, United Kingdom: Blackwell Science; 2005.
4.Daniels GL. Human Blood Groups (2nd ed). Oxford, United Kingdom: Blackwell Science; 2002.
5.Williams TN. Human red cell polymorphisms and malaria. Curr Opin Microbiol. 2006;9:388–394.[CrossRef][Medline] [Order article via Infotrieve]
6.Wells S. The Journey of Man: A Genetic Odyssey. Princeton, NJ: Princeton University Press; 2002.
7.Yamamoto F, Clausen H, White T, et al. Molecular genetic basis of the histo-blood group ABO system. Nature (Lond). 1990;345(6272):229–233.[CrossRef][Medline] [Order article via Infotrieve]
8.Jenkins PV, O'Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all? Transfusion. 2006;46(10):1836–1844.[CrossRef][Medline] [Order article via Infotrieve]
9.Trégouët D-A, Heath S, Saut N, et al. Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach. Blood. 2009;113(21):5298–5303. [Abstract/Free Full Text]
10.Kamphuisen PW, Eikenboom JCJ, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol. 2001;21(5):731–738. [Free Full Text]
11.Gallinaro L, Cattini MG, Sztukowska M, et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood. 2008;111(7):3540–3545. [Abstract/Free Full Text]
12.Zivelin A, Mor-Cohen R, Kovalsky V, et al. Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago. Blood. 2006;107(12):4666–4668. [Abstract/Free Full Text]
13.Lindqvist PG, Dahlback B. Carriership of factor V Leiden and evolutionary selection advantage. Curr Med Chem. 2008;15(15):1541–1544.[CrossRef][Medline] [Order article via Infotrieve]
14.Cserti CM, Dzik WH. The ABO blood group system and Plasmodium falciparum malaria. Blood. 2007;110(7):2250–2258. [Abstract/Free Full Text]
15.Loscertales MP, Owens S, O'Donnell J, et al. ABO blood group phenotypes and Plasmodium falciparum malaria: unlocking a pivotal mechanism. Adv Parasitol. 2007;65:1–50.[CrossRef][Medline] [Order article via Infotrieve]
16.Rowe JA, Opi DH, Williams TN. Blood groups and malaria: fresh insights into pathogenesis and identification of targets for intervention. Curr Opin Hematol. 2009;16(6):480–487.[CrossRef][Medline] [Order article via Infotrieve]
17.Rich SM, Leendertz F, Xu G, et al. The origin of malignant malaria. Proc Natl Acad Sci U S A. 2009;106(35):14902–14907. [Abstract/Free Full Text]
18.Fry AE, Griffiths MJ, Auburn S, et al. Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria. Hum Mol Genet. 2008;17(4):567–576. [Abstract/Free Full Text]
19.Rowe JA, Handel IG, Thera MA, et al. Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting. Proc Natl Acad Sci U S A. 2007;104(44):17471–17476. [Abstract/Free Full Text]
20.Harris JB, Khan AI, LaRocque RC, et al. Blood group, immunity, and risk of infection with Vibrio cholerae in an area of endemicity. Infect Immun. 2005;73(11):7422–7427. [Abstract/Free Full Text]
21.Glass RI, Holmgren J, Haley CE, et al. Predisposition for cholera of individuals with O blood group. Possible evolutionary significance. Am J Epidemiol. 1985;121(6):791–796. [Abstract/Free Full Text]
22.Kaper JB, Morris JG, Levin MM. Cholera. Clin Microbiol Rev. 1995;8(1):48–86. [Abstract/Free Full Text]
23.Blackwell CC, Dundas S, James VS, et al. Blood group and susceptibility to disease caused by Escherichia coli O157. J Infect Dis. 2002;185(3):393–396.[CrossRef][Medline] [Order article via Infotrieve]
24.Azevêdo E, Kreiger H, Morton NE. Smallpox and the ABO blood groups in Brazil. Am J Hum Genet. 1964;16:451–453.[Medline] [Order article via Infotrieve]
25.Duncan SR, Scott S, Duncan CJ. Reappraisal of the historical selective pressures for the CCR5-delta32 mutation. J Med Genet. 2005;42(3):205–208. [Abstract/Free Full Text]
26.Cohn SK Jr, Weaver LT. The Black Death and AIDS: CCR5 delta 32 in genetics and history. Q J Med. 2006;99(8):497–503.
27.Oriol R, Danilovs J, Hawkins BR. A new genetic model proposing that the Se gene is a structural gene closely linked to the H gene. Am J Hum Genet. 1981;33(3):421–431.[Medline] [Order article via Infotrieve]
28.Kukowska-Latallo JF, Larsen RD, Nair RP, et al. A cloned human cDNA determines expression of a mouse stage-specific embryonic antigen and the Lewis blood group alpha(1,3/1,4) fucosyltransferase. J Biol Chem. 1990;4(8):1288–1303.
29.Kelly RJ, Rouquier S, Giorgi D, et al. Sequence and expression of a candidate for the human secretor blood group alpha (1,2) fucosyltransferase gene (FUT2): homozygosity for an enzyme-inactivating nonsense mutation commonly correlates with the non-secretor phenotype. J Biol Chem. 1995;270(9):4640–4649. [Abstract/Free Full Text]
30.Henry S, Mollicone R, Fernandez P, et al. Molecular basis for erythrocyte Le(a+b+) and salivary ABH partial secretor phenotypes: expression of a FUT2 secretor allele with an A>T mutation at nucleotide 385 correlates with reduced alpha(1,2)fucosyltransferase activity. Glycocon J. 1996;13(6):985–993.[CrossRef][Medline] [Order article via Infotrieve]
31.Ferrer-Admetlla A, Sikora M, Laayouni H, et al. A natural history of FUT2 polymorphism in humans. Mol Biol Evol. 2009;26(9):1993–2003. [Abstract/Free Full Text]
32.Aird I, Bentall HH, Mehigan JA, Roberts JAF. The blood groups in relation to peptic ulceration and carcinoma of the colon, rectum, breast and bronchus. BMJ. 1954;2(4883):315. [Free Full Text]
33.Clarke CA, Cowan WK, Edwards JW, et al. The relationship of ABO blood groups to duodenal and gastric ulceration. BMJ. 1955;2(4940):643. [Free Full Text]
34.Björkholm B, Lundin A, Sillen A, et al. Comparison of genetic divergence and fitness between two subclones of Helicobacter pylori. Infect Immun. 2001;69(12):7832–7838. [Abstract/Free Full Text]
35.Borén T, Falk P, Roth KA, et al. Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science. 1993;262(5141):1892. [Abstract/Free Full Text]
36.Aspholm-Hurtig M, Dailide G, Lahmann M, et al. Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin. Science. 2004;305(5683):519–522. [Abstract/Free Full Text]
37.Le Pendu J, Ruvoen-Clouet N, Kindberg E, Svensson L. Mendelian resistance to human norovirus infections. Semin Immunol. 2006;18(6):375–386.[CrossRef][Medline] [Order article via Infotrieve]
38.Thorven M, Grahn A, Hedlund K, et al. A homozygous nonsense mutation (428G-A) in the human secretor (FUT2) gene provides resistance to symptomatic norovirus (CGII) infections. J Virol. 2005;79(24):15351–15355. [Abstract/Free Full Text]
39.Larsson MM, Rydell GE, Grahn A, et al. Antibody prevalence and titre to norovirus (genogroup II) correlate with secretor (FUT2) but not with ABO phenotype or Lewis (FUT3) genotype. J Infect Dis. 2006;194(10):1422–1427.[CrossRef][Medline] [Order article via Infotrieve]
40.Shirato H, Ogawa S, Ito H, et al. Noroviruses distinguish between type 1 and type 2 histo-blood group antigens for binding. J Virol. 2008;82(21):10756–10767. [Abstract/Free Full Text]
41.Carlsson B, Kindberg E, Buesa J, et al. The G428A nonsense mutation in FUT 2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection. PloS One. 2009;4(5):e5593.[CrossRef][Medline] [Order article via Infotrieve]
42.Raza MW, Blackwell CC, Molyneaux P, et al. Association between secretor status and respiratory viral illness. BMJ. 1991;303(6806):815–818. [Abstract/Free Full Text]
43.Ali S, Niang MA, N'doye I, et al. Secretor polymorphism and human immunodeficiency virus infection in Senegalese women. J Infect Dis. 2000;181(2):737–739.[CrossRef][Medline] [Order article via Infotrieve]
44.Kindberg E, Hejdeman B, Bratt G, et al. A nonsense mutation (428G-A) in the fucosyltransferase FUT2 gene affects the progression of HIV-1 infection. AIDS. 2006;20(5):685–689.[Medline] [Order article via Infotrieve]
45.Blackwell CC, Jonsdottir K, Hanson MF, Weir DM. Non-secretion of ABO blood group antigens predisposing to infection by Haemophilus influenzae. Lancet. 1986;2(8508):687.[Medline] [Order article via Infotrieve]
46.Blackwell CC, Jonsdottir K, Hanson M, et al. Non-secretion of ABO antigens predisposing to infection by Neisseria meningitidis and Streptococcus pneumoniae. Lancet. 1986;2(8501):284–285.[CrossRef][Medline] [Order article via Infotrieve]
47.Sheinfeld J, Schaeffer AJ, Cordon-Cardo C, et al. Association of the Lewis blood-group phenotype with recurrent urinary tract infections in women. N Eng J Med. 1989;320(12):773–777.[Abstract]
48.Casals T, Vazquez C, Lazaro C, et al. Cystic fibrosis in the Basque country: high frequency of mutation delta F508 in patients of Basque origin. Am J Hum Genet. 1992;50(2):404–410.[Medline] [Order article via Infotrieve]
49.Taylor-Cousar JL, Zariwala MA, Burch LH, et al. Histo-blood group gene polymorphisms as potential genetic modifiers of infection and cystic fibrosis lung disease severity. PloS One. 2009;4(1):e4270.[CrossRef][Medline] [Order article via Infotrieve]
50.Roberts GF. Comparative Aspects of Haemolytic Disease of the Newborn. London: W. Heinemann; 1957.
51.Levine P, Stetson RE. An unusual case of intragroup agglutination. J Am Med Assoc. 1939;113:126. [Abstract/Free Full Text]
52.Mourant AE, Kope AC, Domaniewska-Sobczak K, The Distribution of the Human Blood Groups and Other Polymorphisms. 1976.
53.Kunierz-Alejska G, Bochenek S. Haemolytic disease of the newborn due to anti-Dia and incidence of the Dia antigen in Poland. Vox Sang. 1992;62(2):124–126.[Medline] [Order article via Infotrieve]
54.Zerjal T, Xue Y, Bertorelle G, et al. The genetic legacy of the Mongols. Am J Hum Genet. 2003;72(3):717–721.[CrossRef][Medline] [Order article via Infotrieve]
55.Mourant AE. The Distribution of the Human Blood Groups. Oxford, United Kingdom: Blackwell Scientific Publications; 1954.
56.Semino O, Passarino G, Oefner PJ, et al. The genetic legacy of Paleolithic Homo sapiens sapiens in extant Europeans: a Y chromosome perspective. Science. 2000;290(5494):1155–1159. [Abstract/Free Full Text]
57.Achilli A, Rengo C, Magri C, et al. The molecular dissection of mtDNA Haplogroup H confirms that the Franco-Cantabrian glacial refuge was a major source for the European gene pool. Am J Hum Genet. 2004;75(5):910–918.[CrossRef][Medline] [Order article via Infotrieve]
58.Gibbons A. Europeans trace ancestry to Paleolithic people. Science. 2000;290(5494):1080–1081. [Free Full Text]
59.Wells RS, Yuldasheva N, Ruzibakiev R, et al. The Eurasian heartland: a continental perspective on Y-chromosome diversity. Proc Natl Acad Sci U S A. 2001;98(18):10244–10249. [Abstract/Free Full Text]
60.Achilli A, Rengo C, Battaglia V, et al. Saami and Berbers—an unexpected mitochondrial DNA link. Am J Hum Genet. 2005;76(5):883–886.[CrossRef][Medline] [Order article via Infotrieve]
61.Colin Y, Cherif-Zahar B, Le Van Kim C, et al. Genetic basis of RhD-positive and Rh D-negative blood group polymorphism as determined by Southern analysis. Blood. 1991;78(10):2747–2752. [Abstract/Free Full Text]
62.Burton NM, Anstee DJ. Structure, function and significance of Rh proteins in red cells. Curr Opin Hematol. 2008;15(6):625–630.[CrossRef][Medline] [Order article via Infotrieve]
63.Busquets J, Castellote J, Torras J, et al. Liver transplantation across Rh blood group barriers increases the risk of biliary complications. J Gastrointest Surg. 2007;11(4):458–463.[CrossRef][Medline] [Order article via Infotrieve]
64.Chérif-Zahar B, Bloy C, Le Van Kim C, et al. Molecular cloning and protein structure of a human blood group Rh polypeptide. Proc Natl Acad Sci U S A. 1990;87(16):6243–6247. [Abstract/Free Full Text]
65.Hanvesakul R, Spencer N, Cook M, et al. Donor HLA-C genotype has a profound impact on the clinical outcome following liver transplantation. Am J Transplant. 2008;8(9):1931–1941.[CrossRef][Medline] [Order article via Infotrieve]
66.Parham P. Immunogenetics of killer cell immunoglobulin-like receptors. Mol Immunol. 2005;42(4):459–462.[CrossRef][Medline] [Order article via Infotrieve]
67.Parham P. MHC class I molecules and KIRS in human history, health and survival. Nat Rev Immunol. 2005;5(3):201–213.[CrossRef][Medline] [Order article via Infotrieve]
68.Santin I, de Nanclares GP, Calvo B, et al. Killer cell immunoglobulin-like receptor (KIR) genes in the Basque population: association study of KIR gene contents with type 1 diabetes mellitus. Hum Immunol. 2006;67(1–2):118–124.[CrossRef][Medline] [Order article via Infotrieve]
69.Flegr J, Klose J, Novotna M, et al. Increased incidence of traffic accidents in Toxoplasma-infected military drivers and protective effect RhD molecule revealed by a large-scale prospective cohort study. BMC Infect Dis. 2009;9:72.[CrossRef][Medline] [Order article via Infotrieve]
70.Singleton BK, Green CA, Avent ND, et al. The presence of an RHD pseudogene containing a 37-base pair duplication and nonsense mutation in Africans with the RhD-negative blood group phenotype. Blood. 2000;95(1):12–18. [Abstract/Free Full Text]
71.Touinssi M, Chapel-Fernandes S, Granier T, et al. Molecular analysis of inactive and active RHD alleles in native Congolese cohorts. Transfusion. 2009;49(7):1353–1360.[CrossRef][Medline] [Order article via Infotrieve]
72.Weatherall DJ. Genetic variation and susceptibility to infection: the red cell and malaria. Br J Haematol. 2008;141(3):276–286.[Medline] [Order article via Infotrieve]
73.Penman BS, Pybus OG, Weatherall DJ, et al. Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean. Proc Natl Acad Sci U S A. 2009;106(50):21242–21246. [Abstract/Free Full Text]
74.Nagel RL, Steinberg MH. Genetics of the beta S gene: origins, epidemiology, and epistasis. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge, MA: Cambridge University Press; 2001:711–755.
75.Chotivanich K, Udomsangpetch R, Pattanapanyasat K, et al. Hemoglobin E: a balanced polymorphism protective against high parasitemias and this severe P falciparum malaria. Blood. 2002;100(4):1172–1176. [Abstract/Free Full Text]
76.Kun JF, Mordmuller B, Lell B, et al. Polymorphism in promoter region of inducible nitric oxide synthase gene and protection against malaria. Lancet. 1998;351(9098):265–266.[CrossRef][Medline] [Order article via Infotrieve]
77.Miller LH, Mason SJ, Clyde DF, et al. The resistance factor to Plasmodium vivax in blacks: the Duffy blood group genotype FyFy. N Engl J Med. 1976;295(6):302–304.[Abstract]
78.Tournamille C, Colin Y, Cartron JP, et al. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy negative individuals. Nat Genet. 1995;10(2):224–228.[CrossRef][Medline] [Order article via Infotrieve]
79.Zimmerman PA, Woolley I, Masinde GL, et al. Emergence of FY*A(null) in a Plasmodium vivax endemic region of Papua New Guinea. Proc Natl Acad Sci U S A. 1999;96(24):13973–13977. [Abstract/Free Full Text]
80.Olsson ML, Smythe JS, Hansson C, et al. The Fyx phenotype is associated with a missense mutation in the Fyb allele predicting Ar89Cys in the Duffy glycoprotein. Br J Haematol. 1998;103(4):1184–1191.[CrossRef][Medline] [Order article via Infotrieve]
81.Ryan JR, Stoute JA, Amon J, et al. Evidence for transmission of Plasmodium vivax among a Duffy antigen negative population in western Kenya. Am J Trop Med Hyg. 2006;75(4):575–581. [Abstract/Free Full Text]
82.Cavasini CE, Mattos LC, Couto AA, et al. Plasmodium vivax infection among Duffy antigen negative individuals from the Brazilian Amazon region: an exception? Trans R Soc Trop Med Hyg. 2007;101(10):1042–1044.[CrossRef][Medline] [Order article via Infotrieve]
83.Hadley TJ, Lu Z, Wasniowska K, et al. Postcapillary venule endothelial cells in kidney express a multispecific chemokine receptor that is structurally and functionally identical to the erythroid isoform, which is the Duffy blood group antigen. J Clin Invest. 1994;94(3):985–991.[Medline] [Order article via Infotrieve]
84.Gardner L, Patterson AM, Ashton BA, et al. The human Duffy antigen binds selected inflammatory but not homeostatic chemokines. Biochem Biophys Res Commun. 2004;321(2):306–312.[CrossRef][Medline] [Order article via Infotrieve]
85.Pruenster M, Mudde L, Bombosi P, et al. The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity. Nat Immunol. 2009;10(1):101–108.[CrossRef][Medline] [Order article via Infotrieve]
86.Segerer S, Regele H, Mack M, et al. The Duffy antigen receptor for chemokines is
Thursday, 27 May 2010
Artificial type 0 blood thanks to embryonic stem cells
After making news on several occasions, scientists may have made a definitive breakthrough, with the first possible transfusion using blood obtained from embryonic stem cells possibly coming within the next three years. The transfusion would be done with type O blood, which can be donated to any patient, and would be obtained by researchers using excess embryos from assisted fertilization. The project, which will be led by Marc Turner of Edinburgh University, will also receive contributions from the Transfusion and Transplant Service of the British National Health Service, as well as the same department and Scotland, and the Welcome Trust, a large charitable group for medical research. The story was reported by the Independent and immediately created controversy and distorted information.
“This isn’t just talk, this time it is a serious breakthrough, and the group behind the project is very serious,” said Professor Carlo Alberto Redi, the scientific director of the IRCCS (Hospital and Medical Treatment) Foundation of the San Matteo General Hospital in Pavia, commenting on the story. Redi emphasized that the capability for the regeneration of the hematopoietic progenitor cells in vitro is well-known and the time is right for real blood to be created, with the term artificial blood no longer appropriate. “When the term synthetic blood is used, people imagine silicone blood, when in reality, in all effects, this is real blood,” said Redi.
IT CANNOT REPLACE BLOOD DONATIONS
The blood that the British researchers plan to use in human treatments in the next three years will only “support and complement” blood donation. Giuseppe Novelli, a geneticist of the University of Rome Tor Vergata, commenting to Adnkronos Salute, was less optimistic. “This is only an announcement, and it seems premature to talk about a victory. This research is starting off well because it has millions in financing and is based on evidence that is very hopeful. But we are only talking about one piece of a very complex puzzle.”
The puzzle, in this case, is represented by the blood that runs through our veins and arteries, “made up of red and white blood cells, platelets, and plasma,” said Novelli. “It is a very complex liquid, which carries out an essential function in our body.” The British study which is currently being launched “is limited to red blood cells, which are certainly not able to resolve all of the problems with transfusions”. The British studies are also developing type O negative blood, a group that is able to donate to any patient without any risk of rejection. “This is blood that can be used, and is used, only in case of emergency.” Novelli continued to say that “the new blood will not be able to replace real blood donation, and I don’t want these announcements to inhibit people from donating blood, or make them underestimate the value or the importance blood donation”.
As for an estimate on how much time it will take to create a synthetic blood that will resolve all problems linked to a lack of donations, Novelli said: “I’m not a magician! Science needs realism, and predictions cannot be made for this type of study. Certainly,” he concluded optimistically, “the progress made with stem cells in the past 12 years since their discovery is a great cause for hope”.
“This isn’t just talk, this time it is a serious breakthrough, and the group behind the project is very serious,” said Professor Carlo Alberto Redi, the scientific director of the IRCCS (Hospital and Medical Treatment) Foundation of the San Matteo General Hospital in Pavia, commenting on the story. Redi emphasized that the capability for the regeneration of the hematopoietic progenitor cells in vitro is well-known and the time is right for real blood to be created, with the term artificial blood no longer appropriate. “When the term synthetic blood is used, people imagine silicone blood, when in reality, in all effects, this is real blood,” said Redi.
IT CANNOT REPLACE BLOOD DONATIONS
The blood that the British researchers plan to use in human treatments in the next three years will only “support and complement” blood donation. Giuseppe Novelli, a geneticist of the University of Rome Tor Vergata, commenting to Adnkronos Salute, was less optimistic. “This is only an announcement, and it seems premature to talk about a victory. This research is starting off well because it has millions in financing and is based on evidence that is very hopeful. But we are only talking about one piece of a very complex puzzle.”
The puzzle, in this case, is represented by the blood that runs through our veins and arteries, “made up of red and white blood cells, platelets, and plasma,” said Novelli. “It is a very complex liquid, which carries out an essential function in our body.” The British study which is currently being launched “is limited to red blood cells, which are certainly not able to resolve all of the problems with transfusions”. The British studies are also developing type O negative blood, a group that is able to donate to any patient without any risk of rejection. “This is blood that can be used, and is used, only in case of emergency.” Novelli continued to say that “the new blood will not be able to replace real blood donation, and I don’t want these announcements to inhibit people from donating blood, or make them underestimate the value or the importance blood donation”.
As for an estimate on how much time it will take to create a synthetic blood that will resolve all problems linked to a lack of donations, Novelli said: “I’m not a magician! Science needs realism, and predictions cannot be made for this type of study. Certainly,” he concluded optimistically, “the progress made with stem cells in the past 12 years since their discovery is a great cause for hope”.
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