DNA sequence variation in ACVR1C encoding the activin receptor-like kinase 7 influences body fat distribution and protects against type 2 diabetes

Emdin, Connor A.; Elosua Llanos, Roberto; Kathiresan, Sekar

doi:http://dx.doi.org/10.2337/db18-0857

DNA sequence variation in ACVR1C encoding the activin receptor-like kinase 7 influences body fat distribution and protects against type 2 diabetes

Citation

Emdin CA, Khera AV, Aragam K, Haas M, Chaffin M, Klarin D. et al. DNA sequence variation in ACVR1C encoding the activin receptor-like kinase 7 influences body fat distribution and protects against type 2 diabetes. Diabetes. 2019 Jan;68(1):226-234. DOI: 10.2337/db18-0857

Abstract

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 ACVR1C (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, 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 DEXA 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 (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; P = 5.6 × 10-13). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in ACVR1C were at 54% lower risk of type 2 diabetes (OR 0.46, 95% 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.