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

journal contribution
posted on 04.04.2019, 08:56 by CA Emdin, AV Khera, K Aragam, M Haas, M Chaffin, D Klarin, P Natarajan, A Bick, SM Zekavat, A Nomura, D Ardissino, JG Wilson, H Schunkert, R McPherson, H Watkins, R Elosua, MJ Bown, NJ Samani, U Baber, J Erdmann, N Gupta, J Danesh, D Saleheen, S Gabriel, S Kathiresan
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.

Funding

This research has been conducted using the UK Biobank resource, application 7089. This work was funded by the National Institutes of Health (R01 HL127564 to S.K.), which had no involvement in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, and approval of the manuscript. This project was also conducted using the Type 2 Diabetes Knowledge Portal resource, which is funded by the Accelerating Medicines Partnership. The REGICOR study was supported by the Spanish Ministry of Economy and Innovation through the Carlos III Health Institute (Red Investigación Cardiovascular RD12/0042, PI09/90506), European Regional Development Fund (ERDF), and the Catalan Research and Technology Innovation Interdepartmental Commission (2014SGR240). Samples for the Leicester cohort were collected as part of projects funded by the British Heart Foundation (British Heart Foundation Family Heart Study, British Heart Foundation grant RG2000010, United Kingdom Aneurysm Growth Study [UKAGS], British Heart Foundation grant CS/14/2/30841) and the National Institute for Health Research (NIHR) (NIHR Leicester Cardiovascular Biomedical Research Unit Biomedical Research Informatics Centre for Cardiovascular Science, IS_BRU_0211_20033). N.J.S. is supported by the British Heart Foundation and is an NIHR Senior Investigator. The Northern German Myocardial Infarction Study is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed) and the FP7 European Union project CVgenes@target (261123). Additional grants were received from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02). This study was also supported through the Deutsche Forschungsgemeinschaft cluster of excellence “Inflammation at Interfaces” and SFB 1123. The Italian ATVB study was supported by a grant from RFPS-2007-3-644382 and Programma di ricerca Regione-Univer

History

Citation

Diabetes, 2019, 68 (1), pp. 226-234

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

AM (Accepted Manuscript)

Published in

Diabetes

Publisher

American Diabetes Association

eissn

1939-327X

Acceptance date

21/10/2018

Copyright date

2018

Available date

04/04/2019

Publisher version

http://diabetes.diabetesjournals.org/content/68/1/226

Language

en

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