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BMI-Associated Mutation With Potential Energy Conservation Role ID'd In Samoans

NEW YORK (GenomeWeb) – A study appearing online today in Nature Genetics suggests that a missense mutation in a fat storage-related gene called CREBRF contributes to elevated body mass index (BMI) in Samoan individuals.

Through a genome-wide association study of more than 3,000 individuals from Samoa, coupled with targeted sequencing focused on a suspicious site in the genome in almost 100 Samoans, researchers from the US, Samoa, and Taiwan narrowed in on the CREBRF variant, which was far more common than usual in the Samoan population.

Their follow-up analyses indicated that the missense change to CREBRF was link to lower-than-usual energy use and elevated fat storage in adipocyte cells — making it an apparent example of a 'thrifty' variant that's valuable when food is not plentiful.

"By carrying out a genome-wide association analysis of BMI in Samoans, we discovered and replicated a strong association with a missense variant in CREBRF that has a much larger effect size than any other known common risk-associated variant for BMI," corresponding author Stephen McGarvey, an epidemiology and anthropology researcher at Brown University, and his co-authors wrote. "Functional evidence from an adipocyte model further demonstrated that CREBRF with this missense variant promotes cellular energy conservation by increasing fat storage and decreasing energy use in comparison to the wild type protein."

With obesity rates on the rise in Samoa, the team set out to search for potential genetic contributors to BMI in the population using Affymetrix array-based genotyping data for 3,072 phenotyped individuals from nearly three-dozen Samoan villages.

After adjusting for population structure and potential relatedness between individuals, the researchers identified a chromosome 5 variant known as rs12513649 with apparent ties to BMI — a SNP that was subsequently validated in another 2,102 individuals from Samoa and American Samoa.

Through targeted sequencing on a stretch of 1.5 million bases surrounding the SNP in 96 Samoans, the researchers uncovered two BMI-associated variants in CREBRF that were in linkage disequilibrium with one another: rs150207780 and a missense change called rs373863828.

The team focused much of its attention on the latter variant, which appeared to be a promising causal mutation based on functional information from the Encyclopedia of DNA Elements. Although this missense mutation was relatively common in Samoans, for example, data from the Exome Aggregation Consortium indicated that it is very rare in individuals from other parts of the world.

Indeed, the researchers found that the missense change to CREBRF showed ties to not only obesity risk, but also to features such as body fat percentage, abdominal and hip circumference, and other BMI-related measures.

Even so, the BMI-associated change to CREBRF did not seem to coincide with metabolic problems such as altered serum triglyceride levels, insulin resistance, or type 2 diabetes risk. On the contrary, they saw hints that diabetes risk and fasting glucose levels may be lower in individuals carrying the missense mutation.

From these and other patterns in the Samoan individuals included in the analysis, the study's authors speculated that "the missense variant does not promote, and may even protect against, obesity-associated comorbidities; however, additional studies will be required to confirm these findings and directly test this hypothesis."

In a series of experiments done on mouse preadipocyte cell lines, the team demonstrated that the CREBRF variant could prompt enhanced fat storage through lipid and triglyceride accumulation, along with declining energy use. In nutrient-deprived cells, on the other hand, expression of the gene jumped, consistent with a potential role for CREBRF in response to food stress.

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