DNA Sequence Variation in 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 BMI (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 (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, = 3.4 × 10), Ile195Thr (-0.15 SD, = 1.0 × 10), Ile482Val (-0.019 SD, = 1.6 × 10), and rs72927479 (-0.035 SD, = 2.6 × 10). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; = 5.6 × 10). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; = 0.006). These findings indicate that variants predicted to lead to loss of gene function influence body fat distribution and protect from type 2 diabetes.