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

Journal article

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.

Authors: Emdin, C; Khera, A; Aragam, K; Haas, M; Chaffin, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Diabetes Association
• Journal: Diabetes
• Volume: 68
• Issue: 1
• Pages: 226-234
• Publication date: 2018-12-20
• Acceptance date: 2018-10-21
• DOI: 10.2337/db18-0857
• EISSN: 1939-327X
• ISSN: 0012-1797
• Pmid: 30389748
• Language: English