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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Our bodies need iron: to form the oxygen-carrying hemoglobin for our red blood cells, maintain our immune systems and keep our muscles and brains functioning properly.

But not too much.  Excess iron can build up in tissues like the liver, heart and pancreas, causing damage and possibly organ failure.

Other than blood loss, there’s no way for the human body to rid itself of excess iron.  The only way to regulate iron levels is by adjusting how much is taken in from food. Low iron levels in the body lead to more absorption in the gut, high iron leads to less.

There are several known genetic mutations that interrupt this iron absorption control mechanism, leading to a condition called hereditary hemochromatosis.  But there are some forms of this disease for which the causative mutation isn’t known, and not everyone with one of the known mutations actually ends up having hemochromatosis.  These observations suggest there are genetic factors affecting iron level control that have yet to be identified.

Two reports published online yesterday by the journal Nature Genetics may have identified one of these additional genetic factors.  Researchers working with mice have found that disrupting the function of the BMP6 gene can lead to iron overload much like that seen in the severe childhood-onset forms of human hemochromatosis.

“Although no human patients with BMP6 mutations have yet been described, our data …suggests that BMP6 mutations or BMP6 gene variants may function as another cause of hereditary hemochromatosis or a modifier of disease penetrance,” write the authors of one of the studies.

23andMe customers can learn whether they are carriers of the mutations that cause adult-onset hemochromatosis using the Health and Traits feature.

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Last week in the Spittoon we reported on a new study that identified an interesting genetic trade-off — a genetic variant known that has one effect on a person’s vulnerability to malaria, and the opposite on susceptibility to HIV infection. The “Duffy negative” version of the gene, which is common among Africans and African Americans, appears to protect a person against malaria but increases vulnerability to infection by HIV.

As it turns out, Duffy is not the only example of a genetic trade-off in humans.  There are many instances of genetic variation throughout the human genome that offer both genetic advantages and disadvantages to their carriers.  Here are some of the most interesting:

1.    Sickle Cell Anemia vs. Malaria

Sickle cell anemia is caused by a genetic mutation that alters the shape of an individual’s red blood cells.  This mutation, called Hb^s, causes red blood cells to take on a sickle-shape, as opposed to the normal round shape.  The sickle-shaped cells then get stuck in the veins and arteries, causing tremendous pain and discomfort.  Sickle cell anemia is recessively inherited, meaning that someone must inherit the Hb^s mutation from both parents in order to have the disease.

Malaria is a disease that kills between 1 and 3 million people worldwide each year, mainly in the tropics.  After scientists noticed similarities between the geographic distribution of sickle cell anemia and malaria, they began to wonder if there was some sort of connection between the two.

Experiments soon confirmed that sickle cell anemia is a sort of genetic Faustian bargain. Recall that individuals with two copies of Hb^s suffer from sickle cell anemia, but people with only one copy of the mutation do not.  They do however, display a resistance to malaria compared with people who have no copies of Hb^s.  Occasionally, a pair of malaria-resistant parents will both pass Hb^s — and thus sickle cell anemia — to their child. But overall, having only one copy improved the survival rate in human history so much that the Hb^s mutation continues to exist in in spite of the disease burden it causes.

2.    Hereditary Hemochromatosis vs. Iron Deficiency

Hereditary hemochromatosis (HH) is a genetic condition in which the body absorbs too much iron from the diet.  This leads to the toxic build-up of iron in the tissues of major organs such as the liver and heart.  Without treatment, HH can lead to organ failure.

Genetic studies have found that HH, like sickle-cell, is a recessive trait. It appears to have evolved about 1,400 years ago, probably in western Europe, at a time when people ate mostly cereal grains — which are very low in iron. Because having some amount of iron in the diet is essential to maintain normal body functions, this was a serious problem.  

During this time period, the ability to store extra iron in the body would have been helpful.  Individuals with HH could take iron from foods when it was available, and then store it in the organ tissues, dipping into those reserves when the supply of iron-rich foods was low.  Today, however, iron is much more abundant. It is an excess of iron, not a lack of it, that threatens the health of people with HH.

3.    The Paleolithic Diet vs. Obesity

Why is it that humans crave the very foods that are unhealthy?  Why do we prefer donuts and candy to celery and spinach?  Like hereditary hemochromatosis, the source of this cruel irony lies in the history of our species.

The human brain is a very expensive organ to maintain.  It requires a lot of energy to keep all the synapses working correctly, and simply feasting on celery would not do the trick.  Hundreds of thousands of years ago, our ancestors began eating meat as a way to get the required energy their brains needed.  Meat is high in the energy that humans needed to survive, and also in long-chain polyunsaturated fats, which are essential to maintenance of brain tissue.  Bone marrow, the fatty substance inside long bones, is also high in fat and calories, and was thus another prized item in our ancestors’ early diet.  

Because foods high in fat and calories were so important to our ancestors, they would have searched them out and evolved a natural preference for them.  Their bodies would have evolved to store any excess fat, in case there were was a long hiatus until the next piece of meat or bone marrow came their way. 

This ‘thrifty’ metabolic approach to fat has persisted to the present day, despite drastic changes in the way we feed ourselves.  Now, instead of searching constantly for food we have seemingly unlimited access to Twinkies, beer and other high-calorie delights.  But our bodies are still storing the excess fat.

The genetics of obesity are complicated, and by no means can they be fully explained by our ancestors’ diet. But the dramatic change in the human diet since the Stone Age does help explain our cravings from an evolutionary perspective.

Variations in the human genome are full of examples such as these: genetic mutations that are beneficial in some ways but harmful in others, or that used to be beneficial, but now result in an increased waistline.  Understanding these genetic ‘trade-offs’ is helpful to understanding the history of the human genome, and could be helpful in tackling conditions such as sickle-cell anemia, hereditary hemochromatosis, obesity and many others.

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