CREBRT variant increases obesity yet decreases risk of T2D in Samoans (??)

There are many epidemiological studies showing a link between obesity and type-2 diabetes (T2D). This intriguing Nat Genet paper and News-N-Views editorial [attached] describes an exception to that rule.

Samoans are a unique founder population, in part because of their high prevalence of obesity. This makes them well suited for identifying new genetic contributors to obesity. Authors conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovering a single-nucleotide (SNP) variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10–14). Authors replicated the association in 2,102 additional Samoans (P = 1.2 × 10–9). Using a second cohort having a number of samples fewer than the first cohort … might explain the differences in P-value, i.e. P-values might not reach statistical significance for GWAS if the cohort size were, say only 100 or 500 individuals.

Also, targeted sequencing identified a strongly associated missense variant in the CREBRF gene, rs373863828 (p.Arg457Gln), which revealed a meta P-value of 1.4 × 10–20. Although this variant is extremely rare in other populations, interestingly, it is common in Samoans (frequency = 0.259), with an effect-size much larger than that of any other known common BMI risk variant (1.36 – 1.45 kg/m2 per copy of the risk-associated allele). In comparison to consensus CREBRF protein, the Arg457Gln variant, when over-expressed selectively, decreases energy use and increases fat storage in an adipocyte cell model. These findings, in combination with evidence of positive selection of the allele encoding p.Arg457Gln among Samoans, … support the “thrifty gene variant” hypothesis, first proposed by Gianfranco, then later used by geneticist James V Neel to explain why certain modern-day populations, or sub-subpopulations, are at higher risk for developing T2D. 

Nat Genet  Sept 2o16; 48: 1049–1054 [article] and News-N-Views pp 976-978



Yes, I know, personally, about your (long interest in, and) history in working on this Samoan adiposity project, and I’m aware of your recent publicity throughout the University Cincinnati Medical Center.

So, let me share this information with the “other GEITP Emailing List” (which is ‘blind-copied’ and ~4 times larger than the within-Cincinnati Emailing List).   

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