Samoan 'Obesity' Gene Found in Half of Population There

Veronica Hackethal, MD

August 03, 2016

Researchers have discovered a new genetic mutation carried by almost half of Samoans that promotes more efficient fat storage and appears to be associated with about a 35% higher odds of being overweight/obese compared with not having the gene variant. The findings are outlined in a paper published online July 25 in Nature Genetics.

Obesity rates in Samoa are among the highest in the world. In 2010, 91% of Samoan women and 80% of Samoan men were overweight or obese (using Polynesian cutoffs, body mass index [BMI] > 26 kg/m2), according to background information in the article.

Results also suggest that the genetic mutation had been "positively selected" for in the Samoan population, which may provide support for the "thrifty-gene" hypothesis in human obesity.

That hypothesis holds that a genetic variation promoting fat storage can be advantageous during times of starvation but contributes to obesity and metabolic diseases during times of nutritional excess. Three thousand years of cross-ocean migration in Polynesia may have provided a selective advantage for a genetic variant favoring obesity.

Europeans and Africans do not appear to carry the newly identified genetic variant, and it is found only at very low frequencies in East Asians. However, studies in over 5000 Samoans suggest that roughly half of the population there may carry the genetic mutation.

Those who have the mutation have higher BMIs but paradoxically lower rates of diabetes than those without it. Still, rates of diabetes among Samoans outrank most other countries in the world.

Just Because You Are Samoan Doesn't Mean You Have to Be Obese

However, senior author Steven McGarvey, PhD, of Brown University, Providence, Rhode Island, highlighted how the environment and shifting away from the traditional lifestyles may affect biology. Transitioning to more calorie-dense processed foods and decreased physical activity may tip the balance toward obesity in at-risk individuals who carry the genetic variation.

"Samoans weren't obese 200 years ago," he notes in a press release from his institution. "The gene hasn't changed that rapidly — it's the nutritional environment that changed that rapidly."

However, he warned against assuming that the genetic variant inevitably leads to obesity.

"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 says. While the elevated risk associated with this variant is much greater than any other known common BMI risk variant, overall it explains only about 2% of the variation in BMI among Samoans, he explains.

So "Don't take this as, 'You are Samoan, you are fated to be obese.' 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."

Missense Mutation Strongly Associated With BMI…

Dr McGarvey and colleagues conducted a genomewide-association study of 659,492 genetic markers in 3072 individuals living in 33 villages in Samoa (the discovery sample). They also collected data on BMI and cardiovascular and metabolic health. The analysis uncovered a genetic variant, rs12513649, that was strongly linked to increased BMI (P = 5.3 x 10-14). Testing the association in a replication sample of 2102 other Samoans yielded similar results (P = 1.2 x 10-9).

They then used more precise, targeted sequencing, which identified a strongly associated missense mutation in the CREBRF gene on chromosome 5. When they genotyped the missense variant, results showed a highly significant association with BMI (discovery sample: P = 7.0 x 10-13; replication sample: P = 3.5 x 10–9; combined meta-analysis: P = 1.4 x 10-20).

And the missense mutation's effect on BMI was greater than any other known genetic variant associated with BMI. Each copy of the mutated gene increased BMI by 1.36 kg/m2 in the discovery sample and by 1.45 kg/m2 in the replication sample.

Further analyses showed that the missense mutation lay in a highly conserved part of the CREBRF gene and had a high probability of being damaging. While the normal, wild-type gene codes for arginine, the missense mutation was found to code for glutamine.

When the researchers evaluated the missense mutation in a mouse model of fat cells, the variant increased lipid and triglyceride accumulation and decreased cellular energy metabolism. Basically, the mutation increased fat storage while less energy was utilized than with the normal version of the gene.

…but Was Associated With Lower Risk of Diabetes

Interestingly, individuals who carried the missense mutation actually had a lower risk of diabetes (discovery cohort: odds ratio [OR], 0.586; P = 6.68 x 10-9) or showed a trend toward lower diabetes risk (replication cohort: OR, 0.742; P = 0.029) than those without the mutation.

The variant was also linked to moderately though significantly lower fasting glucose in those without diabetes (discovery cohort P = 9.5 x 10-5; replication cohort P = 8.8 x 10-4).

Based on these data, the authors hypothesize that the variant may not promote and may somehow even protect against obesity-related disorders like diabetes.

Additional studies are required to explore this finding, they say.

"Such research is urgently needed to inform decisions about how to use knowledge of this obesity risk variant to benefit Samoans at both individual and population health levels and to determine how this discovery might contribute to the understanding and treatment of more common obesity in general," they conclude.

Dr McGarvey and some coauthors are listed as inventors on a provisional patent application covering aspects of this work that has been filed with the US Patent and Trademark Office.

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Nature Genetics. Published online July 25 2016. Abstract

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