Newly Identified 'Thrifty' Genetic Variant May Explain Samoan Obesity

CINCINNATI—A new study involving researchers at the University of Cincinnati (UC) reports that a newly discovered genetic variant, affecting energy metabolism and fat storage, may partly explain why Samoans, a semi-isolated Polynesian population, have among the world's highest levels of obesity. 

The research—published in Nature Genetics and led by scientists at UC, Brown University, the University of Pittsburgh and Yale University as well as Samoan government officials—suggests that nearly half of Samoans have this significant genetic variant, found on chromosome 5, which contributes to obesity risk by up to 35 percent, when coupled with poor diet and a sedentary lifestyle. 

"We have identified a novel genetic variant in a gene, not yet known as an obvious candidate for obesity, that is strongly associated with body-mass index (BMI) in Samoans," said Ranjan Deka, PhD, a professor in the Department of Environmental Health at the UC College of Medicine, and one of the lead investigators of the study. In laboratory cell models, this variant promoted more efficient storage of fat, lipid accumulation and energy utilization, supporting a "thrifty" gene hypothesis for human obesity. 

"While the variant helps to explain why 80 percent of Samoan men and 91 percent of women were overweight (studied in 2010), it is by no means a dominant factor—this variant is just one part of the many reasons for the high levels of BMI and obesity among the Samoans," says Stephen McGarvey, PhD, professor in the Brown University School of Public Health, corresponding author of the paper and a long-time collaborator of Deka in genetic epidemiology studies in Samoa. 

Body measurements, cardiovascular and metabolic health indicators from blood samples were collected from over 3,000 Samoan participants living in 33 villages throughout Samoa in 2010 by a field team led by Nicola Hawley, PhD, an assistant professor at Yale University. The blood samples were processed in makeshift laboratories while on the island, and shipped to Deka's laboratory at UC where DNA was extracted and tested (genotyped) for almost 1 million genetic markers across the entire genome of each person. Guangyun Sun, PhD, a senior research associate at UC, led the genotyping experiments under Deka's supervision. The genotype data was analyzed by statistical geneticists, Daniel Weeks and Ryan Minster, professors at the University of Pittsburgh Graduate School of Public Health. This collaborative group of investigators identified the genetic variant on chromosome 5 with a robust signal of association with BMI.

The identified variant, however, was not located in any known gene and its association could have been driven by its vicinity "with a neighboring variant—the actual variant associated with obesity. This required further study of variants in the region," says Deka. 

"The Samoan genome had not been sequenced; we didn't initially have complete data on that," he continued. "First we looked at it beside other sequenced populations and found nothing remarkable. We then secured NIH funding to sequence 96 Samoan DNA samples which revealed a mutation, called rs373863828, in the CREBRF gene, which is statistically linked to the originally identified variant. This was the first associated variant—in the 96 people, we found that this was very significantly associated with the same traits of increased BMI." 

He said this variant was then genotyped in over 5,000 Samoan individuals, which confirmed the association with increased BMI. A team of molecular geneticists, led by Zsolt Urban, PhD and Erin Kershaw, MD, at the University of Pittsburgh then used a laboratory model of animal fat cells to determine what happens when the mutation was introduced to the fat cells and found that more fat was stored more efficiently. "Our hypothesis is that this is a 'thrifty' variant that conserves energy," Deka says. "Samoan predecessors came from Southeast Asia about 5,000 years ago. During that time of difficult migration, their bodies needed more energy conservation?this variant helped them to store fat and energy, and then natural selection helped in maintaining this variant in the population.

"Now, so much energy, or food, is readily available to us; such a variant may be more pre-disposed to causing obesity." 

Deka says the frequency of this variant is high in Samoans and is almost completely absent in other populations.

"The finding is very strong—we have identified a gene that is strongly associated with obesity with new insights into the etiology of human obesity, but we need further proof," he says, adding a caution that "other factors, such as life style pattern, diet, physical activity and environmental exposures are important and genetic variants interact with these factors influencing obesity."