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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Scientists who are studying mice with a mutation that makes them resistant to obesity even in the face of a high-fat diet may have identified a new way to treat both obesity and diabetes.

Carrying extra weight is known to trigger a state of chronic, low-grade inflammation in the body, which can lead to insulin resistance and, in turn, diabetes.  When scientists at the University of Michigan discovered that an inflammatory protein called IKKε seemed to be a key step in this pathway, they theorized that they could protect mice fed a high-fat diet from developing signs of diabetes by genetically engineering them to lack the protein.

Much to the researchers’ surprise, IKKε knockout mice were spared from not only from chronic inflammation and insulin resistance⎯they also stayed relatively slim even when fed a lard-like chow with 45% of its calories from fat. After three months on this diet, normal mice gained 20 grams, while the IKKε-deficient mice gained only 12 grams.

“We’ve studied other genes associated with obesity … but this is the first one we’ve found that, when deleted, stops the animal from gaining weight.  The fact that you can disrupt all the effects of a high-fat diet by deleting this one gene in mice is pretty interesting and surprising,” said the study’s senior author, Alan Saltiel, in a statement.

The results were published this week in the journal Cell.

Saltiel’s lab is already working to find drugs that inhibit IKKε and could someday be used to prevent obesity and diabetes in humans.  He estimates that new treatments could be available in about a decade, once successful candidate compounds are identified.

But finding a compound that inhibits IKKε isn’t the only obstacle on the road from the lab to the pharmacy.  Researchers will also need to confirm that IKKe works in humans the same way it does in mice.

Then there’s the issue of safety.  Mice lacking the IKKe gene were protected from obesity and related complications, but they were more susceptible to lethal viral infections than their normal littermates⎯a complication that would need to be carefully evaluated before any attempt to reduce IKKε activity is undertaken in humans.

Image: George Shuklin

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Not surprisingly, there has been intense interest in the genetics of obesity in recent years.  Obesity is a major health problem, resulting in tens of thousands of premature deaths and billions of dollars in healthcare costs each year in the United States, and it is known from twin and family studies that weight is a highly heritable trait.

The genetic mutations and variations identified so far explain only a small percentage of the variability in body mass seen in the population.  Some exciting clues have been found, however, as to why some people are more prone to obesity than others and how this might be counteracted.  But new research, published online this week in the American Journal of Human Genetics, shows that caution must be taken in moving from genetic discoveries to drug development.

Variations in the FTO gene have consistently been associated with obesity. On average, people who carry two copies of the “risky” version of this gene weigh six to eight pounds more than those who carry none. Mice completely lacking the FTO gene were shown to be leaner than their normal littermates, despite being less active.  These results have led some to suggest that inhibiting the FTO protein with a drug could be a good for obesity treatment or prevention.

(23andMe customers can see their FTO data in the Obesity Research Report.)

But an international team of researchers led by Sarah Boissel of the Université Paris Descartes in France has found that a mutation that interferes with the function of the FTO protein is associated with a lethal genetic condition.  Members of a large, inbred Palestinian family born with two copies of this mutation had multiple developmental abnormalities and died before the age of three.  Based on their results, Boissel and her colleagues warn that any research exploring the use of FTO inhibitors as obesity treatments must include a “careful assessment” of the potential to cause birth defects and other toxic side effects.

More about FTO:

SNPwatch: Gene Variant Linked to Obesity Affects Food Choices in Children

It’s Not Genes or Environment, It’s Genes AND Environment

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It’s no secret that obesity rates are rising — quickly.  Between 2000 and 2005 the prevalence of obesity rose by 24%.  Extreme obesity increased by more than 50%.  If current trends continue, more than half of all Americans will be clinically obese by the year 2030.

Rapid changes in the prevalence of a disorder suggest that environmental rather than genetic factors are to blame. But scientists know from twin and adoption studies that body mass index (BMI) is highly heritable.  So which is it: nature or nurture?

As with many aspects of human health, it’s both.  Some people have the bad luck to have inherited genetic variations that together with the modern environment – sedentary jobs and hobbies, easy access to calorie-dense foods – create the perfect storm for the onset of obesity.

Changing the environmental factors that lead to obesity in some people seems simple enough – more exercise, less food.  But public health campaigns touting these commonsense fixes have had little effect against the obesity epidemic. By understanding the genetic aspects of obesity, and how they interact with the environment, scientists may be able to develop more effective treatments and prevention strategies.

In the July issue of Nature Reviews Genetics Andrew J. Walley of Imperial College London and colleagues review the current state of obesity genetics research.  While much progress has been made, the authors make it clear that there is still a long way to go, as the genes identified thus far explain only a tiny fraction of the total genetic component of obesity.

One key to future advancements in obesity genetics research, say Walley et al., lies in improvements to current genomewide association study (GWAS) methods.

First, the authors recommend that researchers focus on recruiting extremely obese people for their studies to increase the likelihood of finding genes with large effects. They also suggest that scientists should stop using BMI as their primary measurement of obesity.  While simple and cheap, this method does not take fat distribution or the ratio of fat to muscle into account.  There are more sophisticated methods, such as CT scans, MRI scans and ultrasound imaging, as well as machines that use air displacement to measure body volume and weight and can calculate fat and fat-free body mass.  Technological advances that will reduce the costs associated with genotyping, and ultimately genetic sequencing, are also needed so that larger numbers of subjects can be studied.

Beyond these improvements to current GWAS methods, Walley et al. say studies of more than just common variations are needed.  They suggest that investigations of rare SNPs, copy number variations (duplications, insertions and deletions of DNA) and inherited changes that don’t affect the actual DNA sequence will be needed to fully understand the genetics of obesity.

There are several competing theories about the overall biological basis of obesity.  Some suggest that obesity is a disorder of energy balance in the body, while others think regulation of the growth of fat cells is the key.  Still others think obesity may be due to defects in the neurological control of appetite and food intake.  Continued advancements in understanding the genetics of obesity will help scientists tease these theories apart, and hopefully lead to a healthier future.

(23andMe customers can check their data for a SNP in the FTO gene in the Obesity Research Report.  So far, this is the genetic variant most strongly associated with the risk of obesity.  There is also an Obesity Preliminary Research Report.)

Related posts in the Spittoon:

SNPwatch: New Obesity SNPs Point To The Brain’s Role In Regulating Appetite

SNPwatch: Gene Variant Linked To Obesity Affects Food Choices In Children

Genetics May Dull Brain’s Pleasure Response To Food, Causing Weight Gain

SNPwatch: Genetic Variants Affect Weight Loss Drug Effectiveness

SNPwatch: Genetic Link Between Obesity and Colorectal Cancer

It’s Not Genes Or Environment, It’s Genes AND Environment

SNPwatch: Researchers Find Genetic Variants That May Influence Risk For Obesity

SNPwatch: MC4R Gene Associated With Body Mass

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Our SNPwatch posts here at The Spittoon are one of our most exciting features. They give our customers the opportunity to connect their genetic data to the newest discoveries, often within just hours of a study’s publication.

Looking ahead to 2009, we can only begin to imagine the exciting discoveries that will be made in genetics. In the meantime, here are a few of our favorite SNPwatches from 2008:

SNPs That Affect Drug Response
We reported on several studies this year that showed the importance of genetic variations in determining how different people react to certain medications.

• A report in Nature Genetics showed that some women with a particular version of a SNP in the NQO1 are less likely to survive breast cancer after treatment with the commonly used chemotherapeutic epirubicin.
• A study by the SEARCH Collaborative Group found that a version of one SNP is associated with an increased risk for myopathy (muscle pain and/or weakness) in people taking cholesterol-lowering drugs called statins.
• Mayo clinic researchers found that the weight loss drug sibutramine (Meridia) is effective only in people with specific versions of three different genes.
• And just this month we brought you news of three studies that showed that a genetic variant known to affect the metabolism of the anti-clotting drug clopidogrel (Plavix) also affects heart attack patients’ risk of a second major cardiovascular event.

Shared SNPs
Sometimes multiple conditions strike the same person or run in families. Several studies published this year showed that shared genetic risk factors may be part of the reason why.

• Obesity is a known risk factor for many cancers. Researchers found that a variant of adiponectin, a hormone released by fat cells, can increase the risk of developing colorectal cancer.
• Other researchers found variants that affect the risk of developing both type 1 diabetes and celiac disease, two autoimmune diseases that tend to cluster together. One of these shared variants is also associated with HIV resistance.
• Finally, a report published this month in the Proceedings of the National Academy of Sciences showed that a single genetic variant can make a person prone to greater indulgence in both smoking and drinking.

SNPs Associated with Risk Factors for Disease
Several studies this year looked beyond disease itself and instead found associations between SNPs and traits known to be risk factors for disease.

• One study found an association between several SNPs and fasting plasma glucose, a measure of how well a person’s body can control blood sugar levels – a process that goes awry in diabetes.
• Another research group reported SNPs associated with glycated hemoglobin levels, a measure of long-term blood sugar control and another factor associated with the risk of developing diabetes.
• The findings of three papers published in Nature Genetics roughly doubled the number of SNPs associated with blood levels of cholesterol and triglycerides, important risk factors for cardiovascular disease.
• And finally, in a study that looked at behavior instead of metabolic markers, researchers found that a variant in the FTO gene known to increase the risk for obesity affects food choices in children, pushing them towards foods denser in calories.

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In the current issue of Nature Genetics, two teams of researchers identify nine new genetic locations associated with obesity. Almost all of them are within or close to genes that are expressed in the brain, especially the part that regulates appetite.

“This underscores the importance of genes that regulate food intake over those involved in metabolism,” wrote a team of researchers led by Gudmar Thorleiffsson and G. Bragi Walters of deCODE Genetics.

Thorleiffsson et al. performed a two-step study that initially examined more than 30,000 people of European and African American descent from Iceland, Holland and the United States. It then narrowed down the list of promising genetic regions to 11 using a sample of 5,586 Danish individuals. Four of those regions — in or close to the genes FTO, MC4R, BDNF and SH2B1 — were already known to be associated with obesity.

The other Nature Genetics paper, authored by the members of the Genetic Investigation of Anthropometric Traits (GIANT) consortium, initially looked for genetic links to obesity in more than 32,000 people of European descent, and then pursued their most promising leads in a second group of more than 59,000. The GIANT researchers confirmed two well-known obesity associations — the genes FTO and MC4R — and discovered an additional six.

Altogether, the two teams found nine new obesity-associated genetic variants; but none of them had a very substantial effect. For example, even someone who had the riskier version at all six locations found by the GIANT consortium would be only about four pounds heavier compared to average.

There are two possible explanations for the small effect of these new associations. Either there are dozens more associations with similarly small effects, or relatively rare genetic variations are much more important that more common ones in determining a person’s weight. Either way, finding those additional sources of genetic obesity risk is going to require studies even larger than the ones published this week in Nature Genetics.

23andMe customers who want to know their own genotypes at the new obesity-associated variants can use the following chart, which identifies the weight-increasing genotype for each SNP.

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It seems simple enough: if you eat only as many calories as you burn, you won’t pack on the pounds. Yet for many, balancing this equation is anything but easy. Obesity has become one of the most significant public health threats facing the United States and other developed countries. One-third of adults in the United States today can be considered clinically obese.

While lifestyle choices are certainly important, research has shown that genetics plays a significant role in determining a person’s propensity for being overweight or obese. One especially potent variant in the FTO gene has been consistently linked with weight in Europeans.

In a study of Scottish children published online yesterday by the New England Journal of Medicine, researchers suggest that this FTO variant may contribute to obesity by leading kids to chose foods that, pound for pound, pack a more powerful calorie punch.

[23andMe customers can see their data for an FTO SNP equivalent to the one used in this study by referring to the Health and Traits research report on obesity or using the Browse Raw Data feature. The T version of rs3751812 (equivalent to the A version of rs9939609 reported in this study) is associated with obesity]

Seventy-six kids between the ages of four and 10, selected from a larger study of 2,726 children who were having their height, weight, and FTO genotypes evaluated, also had their energy expenditure and food intake measured.

There was no difference in the number of calories burned while at rest between children who carried the higher weight-associated version of FTO and those who did not. Energy burned due to physical activity was actually higher for carriers than non-carriers. This suggests that the FTO variant isn’t affecting the basal metabolism rate or conferring a proclivity for a sedentary lifestyle.

There was also no difference in the total weight of the food ingested by the kids with the version of FTO linked to obesity. But these children did consume more calories than their non-carrier friends. The foods they chose during the test meals had “higher energy density” — they contained more calories per unit weight.

The authors note that most obesity disorders caused by defects in single genes (such as MCR4) affect eating behavior. These new results, and those of other studies (a few examples here, here, here and here), show that the common FTO variant is no different. It is unclear, however, whether FTO affects appetite regulation or the ability to sense how much food has been ingested.

In an accompanying editorial in NEJM, Dr. Rudolph Leibel says that although the proportion of obesity in the general population that can be attributed to variation in the FTO gene region is high, it’s probably still not enough to start using this SNP as a clinical screening tool.

But he goes on to say that in the not-so distant future more variants such as this one will be found and physicians will be able to assess a “score” based on maybe 15 to 20 genes to predict an individual’s risk for obesity.

“The important role that environment plays in enabling or resisting such susceptibility is clear evidence that such risk can be modified,” Leibel concludes.

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Although obesity was seen as a sign of social status during the Renaissance, it’s been known since long before then that being overweight is actually unhealthy. We all know that carrying around extra pounds increases the risk for high blood pressure, diabetes and cardiovascular disease, yet one out of three Americans is obese.

New research, published online today in Science, suggests that for some obese people, genetic variations may desensitize the brain’s reward centers, making food less satisfying and leading to the consumption of more calories followed by the predictable result — weight gain.

When we eat, feelings of pleasure are produced by the release of a chemical called dopamine into the brain. Recent research has shown that the brains of obese people have fewer dopamine-responsive receptors; this deficit may decrease the pleasure obese people get from food and prompt them to overeat in order to compensate.

“Individual differences in how the brain processes food reward have been postulated to play a role in explaining why some, but not all, people are gaining weight in an environment where calories are plentiful. Our finding is exciting because it supports this possibility by demonstrating an association between an abnormal response to food and future weight gain – and it shows that this relationship depends on your genetic make-up,” said study author Dana Small in statement.

Small and her colleagues examined 43 college women and 33 adolescent girls using functional magnetic resonance imaging scans, which analyze brain activation by measuring blood flow in the brain, while the study subjects tasted either a chocolate milkshake or a flavorless solution.

In both study groups, women with higher body mass indices (BMI) had lower levels of activation in dopamine-responsive areas of their brains as they tasted the milkshake. This relationship was significantly stronger in women with one or two copies of a variation in the dopamine receptor gene DRD2 that scientists call the “Taq1A A1 allele”.

The A1 allele has been associated with fewer dopamine receptors in the brain. Previous research has shown that people with one or two copies of the A1 allele are more likely to be obese. Other traits — such as alcoholism, obsessive-compulsive disorder, and error avoidance – have also been linked to the A1 allele and thus the brain’s reward pathways.

After one year, the researchers found, women with one or two copies of the A1 allele who had also shown lower brain activation in response to food gained more weight, possibly because of their diminished pleasure response.

“Identifying changes in behavior or pharmacological options could correct this reward deficit to prevent and treat obesity,” said the study’s lead author Eric Stice.

(23andMe customers can find out if they have the DRD2 A1 allele by checking their data at rs1800497 with the Browse Raw Data feature. “ A” corresponds to the A1 allele. A “G” at this SNP is called the A2 allele. Customers can also click on the links above to view Research Reports for other traits linked to this variation.)

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Obesity affects about one out of three adults in the United States. And because obese people are at increased risk of high blood pressure, diabetes, cardiovascular disease and other health problems, many authorities consider it one of the most significant public health problems in the developed world.

Of course diet and exercise are important parts of maintaining a healthy weight, but some people need a little more help. Sibutramine (marketed by Abbott Laboratories as Meridia® in the U.S.) is a drug that creates a feeling of fullness, prevents the decline in metabolic rate usually associated with low calorie diets and causes weight loss, especially when combined with behavioral therapy.

But success with sibutramine is variable – for some people it just doesn’t work. New research, published in the October issue of Gastroenterology, shows that genetic differences might be to blame.

“Our results suggest the genetic make-up of patients could predispose their responsiveness to a drug. This could have important implications for the future of personalized molecular-based or individualized medicine,” said the study’s lead author Dr. Michael Camilleri in a statement.

(A video of Dr. Camilleri describing his research can be found at the end of this post.)

Using a sample of 158 overweight and obese people, researchers at the Mayo Clinic tested the effectiveness of sibutramine therapy compared to placebo over 12 weeks. All participants also received behavioral therapy.

The researchers found that weight and body mass index were significantly reduced in patients taking sibutramine compared to placebo, as was expected from previous research. But upon further inspection of the data, the researchers found that only people with certain versions of three different genes experienced significant weight loss.

People with at least one T at the SNP rs5443, in the GNβ3 gene, had success with sibutramine, losing about 13 pounds. People with at least one T at rs5443 and two Cs at rs1800544, in the α2A gene, lost even more weight – more than 17 pounds on average. The drug had no effect if a person had two Cs at rs5443.

The third genetic marker scientists investigated, known in the scientific literature as 5-HTTLPR, is a stretch of DNA that comes in a long and short form. Only people with one or two copies of the short version of this marker had significant weight loss with sibutramine. 23andMe does not currently give data for this type of variant.

“Genetic variations may help select obese patients who are more likely to experience improved outcome with this treatment. Since the different markers were present in almost 50 percent of patients, inclusion of screening for the genetic markers before prescribing the medication may even be cost-effective from a public health perspective,” Camilleri said.

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The connection between obesity and cancer is well established. As many as 25 to 30 percent of several major cancers – colon, breast (postmenopausal), endometrial, kidney, and esophagus – may be accounted for by obesity and physical inactivity. Some studies have also found links between obesity and cancers of the gallbladder, ovaries, and pancreas.

It is not yet clear to scientists, however, how obesity increases the risk for certain cancers. Part of the answer may lie in a hormone released by fat cells — adiponectin. Decreased blood levels of this hormone, which are found in obese people, have been linked with breast, endometrial, prostate and colon cancer.

A new study published today in the Journal of the American Medical Association provides further evidence for adiponectin being the link between obesity and cancer. Researchers have demonstrated that a variant in the gene that encodes the hormone influences the risk of developing colorectal cancer.

Kaklamani et al examined several SNPs in the adiponectin and adiponectin receptor genes in a total of 629 people with colorectal cancer and 855 people without the disease. All subjects except for 37 cases and 37 controls were of European ancestry. The researchers found that people with one or two Gs at rs266729 in the adiponectin gene had 27% lower odds of developing colorectal cancer compared to those with two Cs.

(23andMe customers can look up their data for rs266729 using the Browse Raw Data feature)

According to the report’s senior author, Dr. Boris Pasche, these research findings could help identify people who would benefit from increased colorectal cancer screening.

“Our hope is that we can significantly improve the screening and early detection for this disease, and open new avenues for better understanding the genetic and lifestyle factors that influence colon cancer risk, “ he said in a statement.

Pasche went on to caution that additional studies are needed to confirm whether those without the adiponectin variant that appears to protect people from colorectal cancer will benefit from cancer-prevention lifestyle changes such as diet and exercise.

A different variant in the adiponectin gene was recently identified as a modifier of breast cancer risk in a study co-authored by Pasche. Understanding how variants in this gene influence breast and colorectal cancer risk, and whether the variants affect the risk for other cancers, will require more research.

Colorectal cancer is the second-leading cancer killer of Americans. According to estimates from the American Cancer Society, 149,000 people will be diagnosed with the disease and 50,00 will die this year alone.

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