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EXPERT REACTION: Gene linked to easier body fat storage

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Having a specific gene type tips the balance towards excess fat storage but actually lowers the risk of developing type 2 diabetes, a new Samoan-based study suggests. The researchers also found that while this gene type is globally rare, nearly half of the Samoan people in the study carried it. However the authors strongly caution that this is not evidence that having the gene or being Samoan means unavoidable obesity - they have yet to understand the mechanics of how this gene works and its relationship with other genes or environmental factors such as what food is being eaten.

Journal/conference: Nature Genetics

Organisation/s: Brown University, USA

Media Release

From: Brown University

Newly found, ‘thrifty’ genetic variant influences Samoan obesity

A new study reports that a genetic variant that affects energy metabolism and fat storage partly explains why Samoans have among the world’s highest levels of obesity.

The Samoas’ world-leading rate of obesity is a recent phenomenon, heavily influenced by the globe’s rapid shift to calorie-rich, processed foods and more sedentary lifestyles.

A new study, however, suggests nearly half of Samoans have a newly identified and significant genetic variant that contributes to obesity risk; a variant that had remained undiscovered until researchers focused on the islands’ populations. In cell models in the lab, this “thrifty” variant promoted more efficient storage of more fat.

“A previously unknown genetic variant in an understudied gene is strongly associated with body-mass index (BMI) levels and other adiposity measures in Samoan men and women we studied in 2010,” said Stephen McGarvey, corresponding author of the paper in Nature Genetics and professor in the Brown University School of Public Health. While the variant helps to explain why 80 percent of Samoan men and 91 percent of Samoan women were overweight or obese in 2010, he said, it is by no means a dominant factor.

“Although we have found a genetic variant with a reasonable biological mechanism, this genetic variant is just one part of the many reasons for the high levels of BMI and obesity among Samoans,” he said.

McGarvey with a team of colleagues at the University of Pittsburgh, the University of Cincinnati and Yale University, as well as Samoan government officials, conducted the study. The team pinpointed a single genetic variant on chromosome 5 that, according to the researchers’ estimate, is associated with about 35 percent higher odds of being obese compared to not having the gene variant.

While this elevated risk is much greater than any other known common BMI risk variant, overall it explains only about 2 percent of the variation in BMI among Samoans. Other factors such as diet, physical activity and early life

nutrition and growth are important, and their influences on obesity in the context of this gene variant will be investigated in future studies, McGarvey said.

In several independent samples of people from the islands, totaling more than 5,000 individuals studied since the 1990s, 7 percent of volunteers had two copies of the mutation and another 38 percent had one copy. The other 55 percent of Samoans in the study did not have the variant.

Those with it were more likely to have a higher BMI than those who didn’t have it. At the same time, those with the variant were less likely to have developed Type 2 diabetes. Nevertheless, Samoans also have among the world’s highest rates of that condition.

Meanwhile, the variant is virtually nonexistent in African and European populations, McGarvey said, and is present at only very low frequency among East Asians.

Vetting a variant

Body measurements, cardiovascular and metabolic health indicators from blood samples were collected from participants living in 33 villages throughout Samoa in 2010 by a field team led by Nicola Hawley, formerly of Brown and now an assistant professor at Yale University. Blood samples were processed in makeshift laboratories in villages and shipped to the University of Cincinnati where DNA was extracted. There, the DNA specimens were tested (also known as genotyped) for almost 1 million gene variants across the entire genome of each person for over 3,000 Samoan adults. Ranjan Deka, a long-time collaborator with McGarvey in genetic epidemiology studies in Samoans, and his colleague, Guangyun Sun, led the work.

Statistical geneticists Ryan Minster and Daniel Weeks at the University of Pittsburgh Graduate School of Public Health performed analyses using the genotype information to look for signals across the whole genome that genetic variants might be associated with BMI. They found that one region of chromosome 5 was strongly associated. The team drilled down in that region using more precise DNA sequencing, imputation (genotype prediction), and follow-up genotyping methods in the 2010 sample and replication samples from McGarvey’s earlier Samoan studies. They pinpointed a “missense” mutation called “rs373863828” in the CREBRF gene as the variant associated with higher BMI. The effect of the mutation, the team found, was that it causes the gene’s code to specify the amino acid glutamine in a protein when the unmutated gene would normally specify arginine.

But the team needed to identify the biological mechanisms that might be responsible for this genetic association with BMI.

They turned to University of Pittsburgh molecular geneticist Zsolt Urban and endocrinologist Erin Kershaw, who used a laboratory model of mouse fat cells to determine what happens when the novel missense mutation was introduced into the fat cells. Along with Chi-Ting Su, they found that the fat cells exposed to the missense mutation stored more fats and did so more efficiently, using less energy. Moreover, the variant protected the cells against death induced by starvation just as well as the common version of the gene did.

An evolutionary hypothesis

The findings hint at an evolutionary story, McGarvey said, for which much more archaeological, anthropological and biological proof is needed. But the hypothesis goes like this:

The earliest Samoans may have faced considerable food insecurity when sailing to and settling the South Pacific islands. Those who had this gene variant might have been more efficiently able to extract and store energy from the available food. This may have led to natural selection favoring those who carried this “thrifty” gene variant, McGarvey said, and could account for the notable frequency of the variant in contemporary Samoans.

Once modern conveniences like motor vehicles and high-calorie foods became prevalent among Samoans, they, like many people around the world, became more prone to obesity. The rare genetic variant that long had helped them endure food scarcity, the hypothesis goes, now may somewhat exacerbate BMI in a very different lifestyle context.

“Samoans weren’t obese 200 years ago,” he noted. “The gene hasn’t changed that rapidly — it’s the nutritional environment that changed that rapidly.”

One of the findings, led by Weeks of the University of Pittsburgh, is that the pattern of genetic variant in the chromosomal region encompassing the discovered gene variant is consistent with it having been evolutionarily selected for among ancient Samoans.

Regardless of how it came to be, McGarvey cautioned strongly against taking the variant’s discovery to mean that obesity is somehow inevitable for Samoans. At most it may account for a somewhat elevated risk when many other factors such as diet and physical activity come into play.

“Don’t take this as ‘You are Samoan, you are fated to be obese,’” McGarvey said. “We don’t think that’s true. We don’t have any evidence that that’s the case. A healthy diet and physical activity are still key to maintaining a healthy weight.”

The paper’s other authors are Hong Cheng of the University of Cincinnati, Olive D. Buhule and Jerome Li of the University of Pittsburgh and several Samoan scientists and physicians including: Muagututi‘a Sefuiva Reupena, chief of the Bureau of Statistics, Government of Samoa; Satupa‘itea Viali, a medical specialist in Apia, Samoa; John Tuitele, a public health physician in the American Samoa Department of Health; and Take Naseri, a physician and director of the Ministry of Health, Government of Samoa, in Apia, Samoa.

The National Institutes of Health and Brown University funded the study.

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Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Professor Jim Mann, professor in human nutrition and medicine, University of Otago, director, Healthier Lives National Science Challenge

This is a fascinating discovery but it is important to emphasize that it is not going to help the public health problem resulting from diabetes and obesity anytime soon.

Public health measures aimed at reducing intake of inappropriate foods are still the only hope in the immediate future.

Last updated: 03 Nov 2016 7:53pm
Dr Ofa Dewes, researcher in Pacific Health at the School of Population Health at the University of Auckland, researcher at the Maurice Wilkins Centre

Obesity continues to be disproportionately prevalent among Pacific children and adults when compared with other population groups in New Zealand, and is a major risk factor for developing noncommunicable diseases (NCDs) such as type 2 diabetes. These are priority health issues facing Pacific people living in New Zealand, and in the Pacific region.

Moreover, there is a growing interest among Pacific communities to understand why some people are predisposed to obesity and/or NCDs and others are not even though they live in the same environment and follow similar lifestyles.

The recent scientific discovery of the gene in an ethnic-specific Pacific Polynesian population and its correlation with increased weight is undoubtedly an important finding that has implications for research with Pacific communities to inform prevention and treatment intervention strategies, policy, and health services.

Further studies to better understand the genetic variants and causes of obesity among ethnic-specific Pacific populations, and community engagement to raise awareness, advocacy and knowledge-transfer to other population groups in New Zealand and in the Pacific region at risk of obesity and/or NCDs, will be required.

Meanwhile, this scientific discovery and its implications will need to be clearly explained to Pacific communities and stakeholders as a priority, and the New Zealand public as a whole.

Last updated: 03 Nov 2016 7:44pm
Dr Lisa Te Morenga, Senior research fellow in the Department of Human Nutrition, University of Otago

While the identification of a new genetic variant associated with obesity in Samoan people is of considerable interest, the impact of these findings needs to be contextualised.

This gene explains about 1-2% of the variance in BMI in the sample populations. Since 1980 the prevalence of obesity in Samoan adults has increased by approximately 18%. Today 46% of Samoan men and 69% of Samoan women are classified as obese. This corresponds with a 47% increase in the availability of food energy over the same time-frame. There has been a major increase in dietary intakes of energy dense imported foods particularly vegetable oils, meats and sugar-sweetened beverages.

Although genetic studies give us clues as to those who may be more or less at risk of obesity, this becomes rather irrelevant when more than half of the population is obese. The primary target we need to focus on for obesity prevention and reduction is obvious: we need to tackle the obesogenic environment to reduce the availability of highly palatable, cheap, energy dense, nutrient poor processed foods.​

Last updated: 03 Nov 2016 7:03pm
Professor Peter Shepherd, professor of cell signalling at the University of Auckland, principal investigator at the Maurice Wilkins Centre

We have known for a long time that there is a strong genetic component associated with a person’s risk of putting on extra weight.  However, very little is still known about the genes responsible for this so the current study is a major step forward and one that is particularly important for the South Pacific region.

The study has found that a change at a single point in one gene can greatly increase a person’s tendency to store fat.  What this probably means is that when people with this form of the gene eat food, they will deposit more of it as fat tissue than people who don’t have this version of the gene. Further research will be required to confirm this and we also need to understand how common this gene is in other Polynesian communities in New Zealand.  

The finding that Samoan people have a higher incidence of this gene variant than Europeans shows that different groups in our society are facing different challenges in their efforts to reduce the impact of the modern environment. This knowledge is important as it means we now need to think of strategies that take these differences into account, and to develop targeted strategies rather than trying to use a “one size fits all” strategy to tackle the epidemic of obesity and diabetes that is facing our society.

Last updated: 03 Nov 2016 5:42pm
Dr Mike King, Lecturer at the Bioethics Centre, University of Otago

Studies of this type are highly technical, and require very careful reporting. The information in this study, and those like it, can be very valuable. Discovery of genetic influence on the occurrence of health problems can help explain why a problem arises. This knowledge is valuable in itself, but it can also have valuable implications for how best to improve the lives of people affected by ill-health.

However, care is needed not to overstate the role that a gene variant may play in bringing about ill-health, particularly on the basis of evidence in one paper. This paper provides some evidence for a gene variant playing a strong influencing role in occurrence of obesity in one population, but more research is needed to evaluate and confirm this, to provide a thorough account of the metabolic effects of this variant, and, importantly, to determine what influence environmental factors may have on its expression. The authors note this, but all too often these qualifications are relegated to the concluding sentences of media coverage.

It is perhaps easier for simpler, less nuanced, elements of science such as this to be reported, or to be the message taken by readers. We saw this in New Zealand with the research proposing the so-called “warrior gene” hypothesis, which was readily reported and discussed. This research was heavily criticised, but criticism and correction can lag behind communication and acceptance of such simplistic and, in that case, ill-supported claims.

In the present case, the simple elements of the story are genes, obesity and Samoans. Obesity is a phenotype that is generally socially disfavoured, and this research risks creating or strengthening in the minds of others an association between Samoan people and obesity, and therefore promoting or supporting social disfavour and harmful discrimination. The role of environmental factors not only on the claimed function of this gene variant, but also on the occurrence of obesity should always be explained in research of this type. These environmental factors can be cultural, social, economic, and political. They are extremely important, and often influenced by the views and actions of the population in question, and others.

Although it is incorrect, the view that genes exclusively determine phenotypes is common. Therefore research that has the generic title “Gene X strongly influences phenotype Y in the population of Zs” can easily be understood or misinterpreted as expressing or supporting the erroneous view that all or most Zs are of Y phenotype, and this is because of gene X. This type of research is especially problematic, and can be pernicious in its influence, when the phenotype is viewed negatively, as is the case with obesity. Extreme care should be taken in these cases to avoid this sort of miscommunication or misinterpretation.

It would make a refreshing change if more of this type of research focused on genetic factors influencing phenotypes associated with good health, particularly in populations that are subject to genetic or environmental factors that promote ill-health and are at risk of stigmatisation. It is worth noting that one of the gene variants identified in this study showed some evidence of conferring a protective effect against obesity-related comorbidities. This more positive aspect of the research is equally worthy of reportage, but it would be surprising if this occurred; the authors themselves only discuss in middle of their paper, and do not mention it again.

Last updated: 03 Nov 2016 5:02pm

Dr Rinki Murphy, endocrinologist specialising in diabetes and researcher at the University of Auckland, principal investigator with the Maurice Wilkins Centre

This is a very important study with a novel gene variant in CREBRF discovered to be linked with BMI in people of Samoan ancestry.

Interestingly, it was not associated with greater insulin resistance or adverse lipid profile, and the risk of diabetes was actually lower among carriers of this gene variant.

It is important to do further studies to clarify the mechanism by which this novel gene contributes to overall energy balance and at the same time protects against obesity associated metabolic disease such as type 2 diabetes, perhaps by preferentially promoting safe storage of fat away from key organs such as the pancreas and the liver.

We also need further research to see whether this gene variant is prevalent in Māori, to discover how to use knowledge of this genetic obesity risk variant to benefit people of Samoan ancestry at both the individual and population health level, and to determine how this discovery might contribute to the understanding and treatment of obesity and type 2 diabetes in general.

Last updated: 03 Nov 2016 4:53pm
Dr Tony Merriman, geneticist at the University of Otago, principal investigator at the Maurice Wilkins Centre

The Brown University-led study is significant in that it is the first systematic search for obesity genes in a Polynesian population. The gene that was found (CREBRF) is responsible for fat deposition, a gene that hasn’t been reported as responsible for weight control in any other population so far.

It was notable that the variant of the gene correlated with increased weight is very rare globally, but clearly important in the Samoan population. Thus we can regard it as a population-specific variant.

One word of caution here is that this gene is responsible for only about 2% of weight control in the Samoan population, meaning that further genetic studies need to be done to determine the other genetic factors and gain further knowledge on the causes of obesity. Such studies also need to be done in other Polynesian populations, particularly Māori.

Last updated: 03 Nov 2016 4:07pm

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