TY - JOUR
T1 - DNA sequence variation in ACVR1C encoding the activin receptor-like kinase 7 influences body fat distribution and protects against type 2 diabetes
AU - Emdin, Connor A.
AU - Khera, Amit V.
AU - Aragam, Krishna
AU - Haas, Mary
AU - Chaffin, Mark
AU - Klarin, Derek
AU - Natarajan, Pradeep
AU - Bick, Alexander
AU - Zekavat, Seyedeh M.
AU - Nomura, Akihiro
AU - Ardissino, Diego
AU - Wilson, James G.
AU - Schunkert, Heribert
AU - McPherson, Ruth
AU - Watkins, Hugh
AU - Elosua, Roberto
AU - Bown, Matthew J.
AU - Samani, Nilesh J.
AU - Baber, Usman
AU - Erdmann, Jeanette
AU - Gupta, Namrata
AU - Danesh, John
AU - Saleheen, Danish
AU - Gabriel, Stacey
AU - Kathiresan, Sekar
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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 b-cells), which independently associated with reduced WHRadjBMI: Asn150His (20.09 SD, P = 3.4 3 10217), Ile195Thr (20.15 SD, P = 1.0 3 1029), Ile482Val (20.019 SD, P = 1.6 3 1025), and rs72927479 (20.035 SD, P = 2.6 3 10212). 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 3 10213). 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.
AB - 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 b-cells), which independently associated with reduced WHRadjBMI: Asn150His (20.09 SD, P = 3.4 3 10217), Ile195Thr (20.15 SD, P = 1.0 3 1029), Ile482Val (20.019 SD, P = 1.6 3 1025), and rs72927479 (20.035 SD, P = 2.6 3 10212). 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 3 10213). 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.
UR - http://www.scopus.com/inward/record.url?scp=85058885742&partnerID=8YFLogxK
U2 - 10.2337/db18-0857
DO - 10.2337/db18-0857
M3 - Journal articles
C2 - 30389748
AN - SCOPUS:85058885742
SN - 0012-1797
VL - 68
SP - 226
EP - 234
JO - Diabetes
JF - Diabetes
IS - 1
ER -
