There’s no doubt that blood saves lives.  According to the Red Cross, in the United States alone about five million people need a total of 14 million pints of blood each year.  That’s 38,000 pints every day.

But transfusions are not without their dangers.  Among them is transfusion-related acute lung injury (TRALI), a rare but potentially life-threatening condition that happens when there is a clash between donor and recipient blood.  TRALI is one of the major causes of transfusion-association deaths in the developed world.

New research, recently published in the journal Nature Medicine, suggests that many cases of TRALI are due to a difference at just one genetic variation between donor and recipient.  This finding could someday enable screening before a transfusion is done, allowing doctors to reduce the risk of TRALI.

One reason TRALI happens is that a donor’s blood contains antibodies that recognize something in the recipient’s blood as an enemy.  These donor antibodies mount an attack that sets off a chain reaction of immune responses in the recipient’s body, leading to lung injury.  Several triggers for this type of TRALI have been identified.  One of these, the HNA-3 antigen, has repeatedly been associated with severe and fatal TRALI reactions.

HNA-3 comes in two versions: HNA-3a and HNA-3b.  A person whose body expresses only the HNA-3a version can make antibodies against the HNA-3b version if he or she is exposed to it somehow.  Likewise, a person whose body expresses only the HNA-3b version of the protein can end up with antibodies against the HNA-3a version. Someone who expresses both HNA-3a and HNA-3b, as a result of inheriting a different version from each parent, won’t make antibodies against either version.  For reasons that aren’t really understood, only antibodies against the HNA-3a version are relevant when it comes to TRALI.

The most common route of exposure to foreign versions of the HNA-3 antigen is childbirth.  A woman can be exposed to her child’s blood, and if it contains a different version of HNA-3 than her body is used to, she might produce antibodies.  The likelihood that a woman will have antibodies against HNA-3 increases with each birth.

The new research found that the different versions of HNA-3 are due to SNP rs2288904 in the SLC44A2 gene.  Someone who is GG at this SNP will express only HNA-3a.  Someone who is AG will express both the HNA-3a and HNA-3b version.  Finally, someone who is AA at rs2288904 will express only HNA-3b.  The first two genotypes (GG and AG) represent about 95% of the population with European ancestry.  These are the people who are at risk for TRALI if they receive blood from a donor who is part of the 5% of the population that has AA at rs2288904.

(23andMe Complete Edition customers can check their data for rs2288904 using the Browse Raw Data feature.)

Confused?  Here’s an example from my own family that will hopefully make things more clear:

The authors of the new study suggest that their new findings can be used to develop a large-scale screening program that could reduce the risk of TRALI.  Blood donors could be genetically screened to find those who are capable of producing antibodies against HNA-3a (i.e., they are AA at rs2288904).  Alternatively, the new genetic information could help scientists create artificial HNA-3a antigens that could be used in the lab to screen donated blood directly.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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Previously in The Spittoon, we discussed two papers that identified genetic variants associated with hemoglobin levels in circulating blood.

But blood consists of much more than hemoglobin, and it is responsible for much more than just transporting oxygen. This week Nature Genetics published the results of two of the largest blood studies to date, which together identified dozens of new variants associated with nine blood-related traits.

In addition to red blood cells, which carry hemoglobin, whole blood contains white blood cells—a crucial part of our immune system—and platelets, which are important for clotting. All of these cellular components are suspended in a protein-rich plasma that makes up most of the volume of blood, and maintains the pressure needed to deliver the blood’s cargo throughout a person’s body.

Like hemoglobin levels, measurements of other blood traits can be informative about health. An abnormally high white blood cell count and platelet volume have both been linked to an increased risk for heart attack. These measurements can also indicate the presence of infectious disease, immunological disorders or cancers.

Nicole Soranzo and her colleagues in the HaemGen consortium measured hemoglobin concentration (Hb), red blood cell count (RBC), red blood cell volume (MCV), platelet count (PLT), platelet volume (MPV), white blood cell count (WBC), the amount of hemoglobin per red blood cell (mean corpuscular hemoglobin content, or MCH), and the amount of hemoglobin relative to the size of the cell (mean corpuscular hemoglobin concentration, or MCHC) in more than 14,000 healthy individuals from Europe. They found sixteen new genetic associations with blood traits from fifteen genomic regions not previously thought to be involved.

Santhi Ganesh and her colleagues in the CHARGE consortium measured Hb, MCV, RBC, MCH, MCHC, and the percent of red blood cells in whole blood (hematocrit, or Hct) in more than 24,000 Caucasian individuals from the U.S. and Europe. Here, they found nine new associated variants from eleven previously unassociated genomic regions.

(23andMe customers can see their data for the SNPs currently covered by 23andMe’s service using the Browse Raw Data feature. See table at the end of this post.)

One of the advantages of these studies is the number of traits that they analyzed.

“Until now, few genome-wide association studies have looked beyond single traits,” Soranzo’s co-author Christian Geiger said in a press release. “But, through a systematic analysis of correlated traits we can begin to discover such shared genetic variants, forming the basis for understanding how these processes interact to influence health and disease.”

Both teams noted several genomic regions that play a broad role in blood-related health. The HBS1L-MYB, TFR2-EPO, TMPRSS6 and HFE regions were all associated with at least three different traits. These regions have also been connected to fetal hemoglobin levels and the iron-overload condition hemochromatosis. Of these newly associated variants, many are close to genes that present promising candidates for further research.

Soranzo’s team went further by investigating whether two of the variants associated with increased platelet volume (PLT) rs11066301 and rs11065987, were also associated with coronary artery disease. They analyzed these SNPs in about 9,500 people with coronary artery disease and 10,500 healthy controls. They found that at both SNPs, each copy of a G increased odds of coronary artery disease by about 1.15 times.

(23andMe customers can see their data for rs11065987 by using the Browse Raw Data feature. 23andMe does not report on rs11066301, but we do report on rs11066320, which correlates perfectly with rs110066301. For rs110066320, the A allele corresponds to increased PLT and higher odds of coronary artery disease.)

When the researchers looked more closely at the region where rs11066301 and rs11065987 are located, they found a block of ten SNPs that tend to be inherited together, and which are all associated with increased PLT and risk of coronary artery disease. They also confirmed previous findings from other researchers of association between celiac disease and type 1 diabetes with SNPs in this block.

Data for chimpanzees and multiple human populations point to a relatively recent event in human evolution where the above-mentioned genetic variants swept across European populations — but not East Asian or African populations. Because the block of SNPs is located in an area of the genome involved in immune response, the authors suggest that these mutations may have given some populations a survival advantage against infection, despite increasing the risk for certain diseases.

SNPs associated with blood-related traits

* In some cases, 23andMe does not cover the original SNP, so a proxy SNP that correlates perfectly with the original in Europeans is reported instead.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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Doctors routinely order the complete blood count (CBC) for their patients because they can learn a lot about a person’s health by measuring the numbers of different types of blood cells in the circulation, their sizes and the ratios between them.

One component of the CBC is usually a measure of the total amount of hemoglobin, the oxygen carrying protein found in red blood cells.  Low levels of hemoglobin can be a sign of nutritional deficiency, autoimmune disease or bone marrow problems, and may result in fatigue, irregular heartbeat and poor growth in children.  Abnormally high levels of hemoglobin can be caused by heart failure, COPD or kidney cancer and are associated with increased risk of stroke.

New research published online in the journal Nature Genetics this week identifies two SNPs that account for a small amount of the variation in hemoglobin levels seen in the population and may help scientists find new ways to treat blood disorders.

John Chambers and colleagues analyzed the DNA from more than 11,000 Europeans in England and Finland and more than 16,000 Indian Asians living in London.  They found rs855791 and rs198846 both impacted hemoglobin levels.

In both the European and Indian study groups, each A at rs855791 and each G at rs198846 led to an approximately 0.1 gram per deciliter (g/dL) decrease in hemoglobin levels. The normal range for hemoglobin levels in adults is 12 to 18 g/dL.

(23andMe does not currently offer data for rs198846.  Customers can use rs1799945 as a proxy for this SNP.  The C version of rs1799945 corresponds to the lower hemoglobin levels G version of rs198846.)

Approximately 25% of the world’s population has hemoglobin levels low enough to be considered anemic.  The World Health Organization has deemed anemia a severe public health problem in India.  Although nutritional iron deficiencies are a large part of the problem in this and other countries with high levels of anemia, it is interesting to note that the versions of rs855791 and rs198846 that lead to lower hemoglobin levels were found at higher frequencies in the Indian study subjects.

Both SNPs identified in this study are in or near genes involved in regulating the body’s iron levels.

Rs198846 is near the HFE gene.  Mutations in this gene cause hereditary hemochromatosis, a condition that can result in iron overload.  The researchers found, however, that the effect of rs198846 is not related to these mutations.

Rs855791 is located in the TMPRSS6 gene.  Mutations in this gene have been shown to cause a serious form of anemia that does not respond to treatment with oral iron supplements.  Chambers says that learning more about how this gene contributes to hemoglobin levels could lead to new treatments for people suffering from chronic hemoglobin problems.

“The enzyme protein produced by the TMPRSS6 gene is a good target for drug development. Designing a drug that enhances TMPRSS6 activity could augment hemoglobin in people such as cancer and kidney failure patients, who suffer from chronically low levels. A different drug that blocked TMPRSS6 enzyme production might bring down high hemoglobin levels,” he said in a statement.

Several other reports published online this week in Nature Genetics (Benyamin et al., Soranzo et al. and Ganesh et al.) also examined genetic contributions to blood traits.  These will be covered later this week here in the Spittoon.  Benyamin et al. and Ganesh et al. also both found evidence for an association between rs855791 and hemoglobin concentration.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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Not long after Karl Landsteiner first described the different ABO blood types, scientists started looking for associations between blood type and other human traits.  Some of their theories were truly weird (more on these tomorrow!), but some have held up to scientific scrutiny.

Venous Thromboembolism (VTE)
People with non-type O blood (A, B and AB) have been shown to be at increased risk for VTE.  The reason is thought to be that these people have higher levels of the clot-inducing proteins factor VIII and von Willebrand factor in their blood.  Having non-type O blood further raises the already increased risk for VTE in people who carry the Factor V Leiden and prothrombin G20210A mutations.

Cancer
Since the 1950s, scientists have found that people with type O blood have decreased risk for stomach cancer compared to people with type A.  Other cancers (pancreatic, breast, ovarian, cervical) also occur at lower rates in people with type O blood.  No one is quite sure why this is.  It could be that the sugars found on type A blood cells, which are also expressed by other cells in the body, might somehow help cancers grow more aggressively.  Alternatively, some research has shown that regardless of person’s own blood type, tumors express the type A sugars. In people with type A blood, these sugars go unnoticed by the immune system because they are considered normal.  But in people with type O blood, these new sugars are recognized as foreign, spurring the immune system to destroy the tumors.

Stomach Ulcers
Although stomach cancer is less prevalent in people with type O blood, stomach ulcers are more common in people with this blood type.  The sugars that define the different blood types are also found on cells in the gastrointestinal tract.  Research has shown that these sugars influence the ability of H. pylori, a type of bacteria responsible for a large number of stomach ulcers, to attach to the lining of the stomach.  People with type A or B blood (and hence A or B sugars on their stomach cells) have fewer H. pylori receptors than people with type O.

Severe Malaria
In people infected with malaria, more severe disease is seen in those whose red blood cells are induced to form rosettes, large aggregates that block small blood vessels.  Studies have shown that people with type O blood form fewer, smaller and more easily broken up rosettes than people with type A, B or AB blood.  This is probably because the sugars found on the non-O blood cells end up helping to create larger clumps of cells.

Infectious Disease
Some studies have shown that certain bacterial and viral infections are more or less likely in certain blood types.  For example, type A blood has been linked to a predisposition to “glue ear,” which is caused by infection with Pseudomonas aeruginosa. And some studies suggest that people with type O or B blood are less susceptible to smallpox. The research supporting these and other claims of an impact of blood type on infectious diseases are not as strong as the other associations listed above, however.

(23andMe customers can get a prediction of their ABO blood type based on their DNA data through the new ABO Lab feature.)

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When it comes to blood transfusions, what’s good for one person might be deadly for another.

This might seem obvious today, but until 1900 the idea of “blood types” wasn’t understood. A person in need of a transfusion could find himself getting a donation from just about anyone, and sometimes even an animal!

But in 1900 Austrian scientist Karl Landsteiner noticed that when the blood of different people was mixed together the cells would often clump up, a process he correctly attributed to an immune reaction between the two blood samples. By the next year he had used this clumping reaction to define three main types of blood, which he named A, B and O. (The fourth blood type, AB, was identified in 1902 by two other scientists, Decastello and Struli.)

After hundreds of years of performing blood transfusions unguided, scientists finally had what they needed to safely transfer blood between people. In 1907, the first blood transfusion utilizing the new typing techniques was successfully carried out, and by World War I transfusions were being performed safely on a large scale.

But knowing what blood to give someone and having it on hand are two different things.

Blood banks are faced with the daunting task of making sure there is enough blood of the right type for everyone who needs it at all times. Blood type O, the “universal donor,” tends to be overused. This presents a problem for the approximately 40% of Americans are type O and thus can receive only this type in a transfusion. If supplies run low, their lives could be in danger. At the same time, donated blood with the rare B and AB types can sit unused for so long that it becomes outdated and must be discarded.

One solution to managing the blood supply would be to transform all blood into type O, thus making it suitable for everyone. In the early 1980’s scientists found a way to do this using an enzyme from coffee beans that could strip certain sugars off of type B blood cells. Clinical trials showed that this method was safe and effective, but the method itself was too time consuming and costly to ever be of clinical use. New research, however, has identified bacterial enzymes that can carry out this same process more efficiently. Research with this new method is still in progress.

(23andMe customers can get a prediction of their ABO blood type based on their DNA data through the new ABO Lab feature.)

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