DNA Sequence Variation in ACVR1C Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes-Reference-Cited by-同舟云学术

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

Published:2018-11-02 Issue:1 Volume:68 Page:226-234
ISSN:0012-1797
Container-title:Diabetes
language:en
Short-container-title:

Author:

Emdin Connor A.¹²³^ORCID,Khera Amit V.¹²³,Aragam Krishna¹²³,Haas Mary¹²³,Chaffin Mark³,Klarin Derek¹³⁴,Natarajan Pradeep¹²³,Bick Alexander¹³,Zekavat Seyedeh M.¹³⁵,Nomura Akihiro¹²³,Ardissino Diego⁶⁷,Wilson James G.⁸,Schunkert Heribert⁹,McPherson Ruth¹⁰,Watkins Hugh¹¹¹²,Elosua Roberto¹³¹⁴¹⁵,Bown Matthew J.¹⁶,Samani Nilesh J.¹⁶,Baber Usman¹⁷,Erdmann Jeanette¹⁸¹⁹,Gupta Namrata³,Danesh John²⁰²¹²²,Saleheen Danish²³²⁴,Gabriel Stacey³,Kathiresan Sekar¹²³^ORCID

Affiliation:

1. Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA

2. Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA

3. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA

4. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA

5. Yale Medical School and Department of Computational Biology and Bioinformatics, Yale University, New Haven, CT

6. Division of Cardiology, Azienda Ospedaliero–Universitaria di Parma, Parma, Italy

7. Associazione per lo Studio della Trombosi in Cardiologia, Pavia, Italy

8. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS

9. Deutsches Herzzentrum München, Technische Universität München, and Deutsches Zentrum für Herz-Kreislauf-Forschung, München, Germany

10. University of Ottawa Heart Institute, Ottawa, Ontario, Canada

11. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.

12. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.

13. Cardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute, Barcelona, Spain

14. CIBER Enfermedades Cardiovasculares (CIBERCV), Barcelona, Spain

15. Facultat de Medicina, Universitat de Vic-Central de Cataluña, Vic, Spain

16. Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Leicester, U.K.

17. The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY

18. Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany

19. DZHK (German Research Centre for Cardiovascular Research) partner site Hamburg/Lübeck/Kiel, Lübeck, Germany

20. Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, U.K.

21. Wellcome Trust Sanger Institute, Hinxton, Cambridge, U.K.

22. National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge. Cambridge, U.K.

23. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

24. Center for Non-Communicable Diseases, Karachi, Pakistan

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.

Funder

National Institutes of Health

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Link

https://journals.org/diabetes/diabetes/article-pdf/68/1/226/555007/db180857.pdf

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