DNA Sequence Variation in ACVR1C Encoding the Activin-Receptor Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes.

A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene ACVR1C , encoding the activin-receptor like kinase 7 receptor expressed on adipocytes and pancreatic beta cells, which independently associated with reduced WHRadjBMI: Asn150His (-0.09 standard deviations, p=3.4*10-17 ), Ile195Thr (-0.15 SD, p=1.0*10-9 ), Ile482Val (-0.019 SD, p=1.6*10-5 ) and rs72927479 (-0.035 SD, p=2.6*10-12 ). Carriers of these variants exhibited reduced percent abdominal fat in dual energy X-ray imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through ACVR1C was associated with a 30% lower risk of type 2 diabetes (OR 0.70, CI 0.63, 0.77; p = 5.6*10-13 ). In an analysis of exome sequences from 55516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46 CI 0.27, 0.81; p=0.006). These findings indicate that variants predicted to lead to loss of ACVR1C gene function influence body fat distribution and protect from type 2 diabetes.