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

• Published in: Diabetes (New York, N.Y.) Vol. 68; no. 1; pp. 226 - 234
• Main Authors: Emdin, Connor A., Khera, Amit V., Aragam, Krishna, Haas, Mary, Chaffin, Mark, Klarin, Derek, Natarajan, Pradeep, Bick, Alexander, Zekavat, Seyedeh M., Nomura, Akihiro, Ardissino, Diego, Wilson, James G., Schunkert, Heribert, McPherson, Ruth, Watkins, Hugh, Elosua, Roberto, Bown, Matthew J., Samani, Nilesh J., Baber, Usman, Erdmann, Jeanette, Gupta, Namrata, Danesh, John, Saleheen, Danish, Gabriel, Stacey, Kathiresan, Sekar
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.01.2019
• Subjects: Activin; Activin Receptors, Type I - genetics; Adipocytes; Algorithms; Body fat; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Dual energy X-ray absorptiometry; Exome - genetics; Gene expression; Genetic Predisposition to Disease - genetics; Genetics/Genomes/Proteomics/Metabolomics; Genome-Wide Association Study; Hip; Humans; Kinases; Nucleotide sequence; Pancreas; Sequence Analysis, DNA - methods
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db18-0857

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.