We all know people struggling with weight issues. Maybe they’re overweight and can’t seem to lose the pounds no matter what new diet or exercise regime they try. Or, maybe they’re underweight and have a hard time bulking up no matter how many donuts they consume or weights they lift. Clearly, there’s more to your weight than what you eat.

Researchers have been hot on the trail of genetic factors influencing obesity ever since the discovery of the gene coding for leptin, a protein responsible for telling the brain “I’m full.” But just having a genetic variant linked to obesity doesn’t mean stretchy waist pants are a certainty – many factors interact with diet to affect your health.

Several years ago, a team led by Dolores Corella and Jose Ordovas discovered that the rs5082 variant in the APOA2 gene is associated with obesity as well as general food measures like total calorie and protein intake. In a new study published last month in the Archives of Internal Medicine, Corella and Ordovas replicated the association with obesity in three independent populations and determined that the association depends specifically on the amount of saturated fat in the diet. More than 3400 individuals across three population groups – 2532 people of European ancestry and 930 Hispanics from Puerto Rico – participated in the study, providing data on dietary intake, physical activity, body mass index (BMI) and other variables.

In the two European populations, individuals with two copies of the C version of rs5082 had significantly higher calorie intake than individuals with at least one copy of the T version – a finding that echoed their previous work. When Corella and her colleagues looked at BMI, however, they found that rs5082 was significantly associated with higher BMI, but only in individuals who consumed high amounts of saturated fat, irrespective of total calorie intake.

In all three populations, there was no association between rs5082 genotype and BMI in individuals who consumed diets low in saturated fat. Furthermore, there was no significant difference in BMI for individuals who had low intake and individuals who had high intake if they had at least one copy of the T version. But people with the CC genotype who consumed diets high in saturated fat had significantly higher BMI than people with either the TC or TT genotype who also consumed high saturated fat diets. After combining data from the three groups, Corella’s team determined that individuals with the CC genotype who had high saturated fat intake also had about 1.8 times higher odds of obesity than individuals with the T version who consumed similar amounts of saturated fat, total calorie intake being equal.

(23andMe Complete Edition customers can look up their data for rs5082 using the Browse Raw Data feature, where G corresponds to the C version and A corresponds to the T version reported here.)

Although earlier research in animals has implicated APOA2 in obesity, its role in human health has been controversial. In this study, Corella and her team show that saturated fat intake can interact with a genetic variant in APOA2 to increase obesity risk. In fact, the variant makes more of a difference the more saturated fat one consumes. While minimizing saturated fat intake continues to be common sense, in a society characterized by rich diets and increasingly sedentary lifestyles, discoveries like this drive home the fact that genetics and environment together form an intricately interwoven picture of our health.

(Many thanks to TRK for bringing this study to our attention!)

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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Generally when you think about what separates humans from other species, features like upright walking, large brains and language come to mind.

But diet has actually played an enormous role in human evolution. Today at the annual meeting of the American Association for the Advancement of Science, a panel of anthropologists, geneticists and paleontologists got together to discuss how who we are has been shaped by what we eat.

Perhaps the most surprising conclusion was that — despite what some diet gurus may say — there is no “natural” human diet. Not only can humans thrive on a wide variety of diets, from the highly carnivorous fare of nomadic Siberians to the virtually all-potato menu consumed by native Peruvians, but thanks to evolution our species can change its diet surprisingly readily.

“You can find humans living well and healthily from a tremendous diversity of diets,” said William Leonard, an anthropologist at Northwestern University in Evanston, Ill.

But all cultures have one dietary feature in common, said Harvard University primatologist Richard Wrangham — they cook their food. Wrangham believes the advent of cooking during human prehistory was a major evolutionary milestone, because it essentially pre-digested starches and proteins and softened food, helping increase the amount of energy that could be extracted on it. In fact, he pointed out that people in modern technological societies who take up so-called “raw food” diets usually lose substantial amounts of weight.

Many diet books advise following a high-protein, low-carbohydrate diet in order to emulate the eating habits of pre-agricultural humans. Whatever the benefits of such a diet, however, it is clear that in the 10,000 years since the development of farming our genes have responded to the increasing availability of foods such as rice, grains and milk.

“I would say most people who descend from agricultural populations are actually pretty well adapted to a starch diet, because most of the world eats a lot of rice, a lot of corn and a lot of potatoes, said Anne Stone, a geneticist at Arizona State University.

Stone and her colleagues have studied the gene AMY1, which encodes a salivary protein called amylase that breaks down starch. All people have multiple copies of the AMY1 genes. But those from traditionally agricultural populations, such as the Japanese and Europeans, have many more than those from cultures that have never practiced agriculture.

Customers of 23andMe may be able to see the evolutionary effects of an agricultural heritage in their own genetic data. Before people started herding cattle, goats and sheep, the human biological machinery for digesting milk was turned off not long after infancy — perhaps to prevent older children from getting in destructive fights over breast milk. But with herd animals on the scene, when a genetic modification that kept milk digestion functioning into adulthood arose in Europe around 8,000 years ago, it was so beneficial that it eventually spread throughout the continent.

23andMe customers have one modified version of the lactase gene for each A at the SNP rs4988235.

Similar scenarios happened in several other parts of the world as well, so that now many people of European and some of African ancestry can easily digest large amounts of milk.

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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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