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

Connor A. Emdin; Amit V. Khera; Krishna Aragam; Mary Haas; Mark Chaffin; Derek Klarin; Pradeep Natarajan; Alexander Bick; Seyedeh M. Zekavat; Akihiro Nomura; Diego Ardissino; James G. Wilson; Heribert Schunkert; Ruth McPherson; Hugh Watkins; Roberto Elosua; Matthew J. Bown; Nilesh J. Samani; Usman Baber; Jeanette Erdmann; Namrata Gupta; John Danesh; Danish Saleheen; Stacey Gabriel; Sekar Kathiresan

doi:10.2337/db18-0857

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

Connor A. Emdin, Amit V. Khera, Krishna Aragam, Mary Haas, Mark Chaffin, Derek Klarin, Pradeep Natarajan, Alexander Bick, Seyedeh M. Zekavat, Akihiro Nomura, Diego Ardissino, James G. Wilson, Heribert Schunkert, Ruth McPherson, Hugh Watkins, Roberto Elosua, Matthew J. Bown, Nilesh J. Samani, Usman Baber, Jeanette ErdmannNamrata Gupta, John Danesh, Danish Saleheen, Stacey Gabriel, Sekar Kathiresan^*

^*Korrespondierende/r Autor/-in für diese Arbeit

31 Zitate (Scopus)

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 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.

Originalsprache	Englisch
Zeitschrift	Diabetes
Jahrgang	68
Ausgabenummer	1
Seiten (von - bis)	226-234
Seitenumfang	9
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db18-0857
Publikationsstatus	Veröffentlicht - 01.01.2019

Fördermittel

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-Università 2010-2012 Area 1–Strategic Programmes–Regione Emilia-Romagna. Funding for ESP was provided by RC2 HL103010 (HeartGO), RC2 HL102923 (LungGO), and RC2 HL102924 (WHISP). Exome sequencing was performed through RC2 HL102925 (BroadGO) and RC2 HL102926 (SeattleGO). The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. J.G.W. is supported by U54GM115428 from the National Institute of General Medical Sciences. Exome sequencing in ATVB, PROCARDIS, Ottawa, PROMIS, South German Myocardial Infarction Study, and the JHS was supported by 5U54HG003067 (to S.G.). A.V.K. is supported by a K08 from the National Human Genome Research Institute (K08HG010155) and a Junior Faculty Award from the National Lipid Association and has received consulting fees from Amarin. P.N. reports funding from the John S. LaDue Memorial Fellowship at Harvard Medical School and has received consulting fees from Amarin. S.K. is supported by a research scholar award from Massachusetts General Hospital, the Donovan Family Foundation, and R01 HL127564; has received a research grant from Bayer Healthcare and consulting fees from Merck, Novartis, Sanofi, AstraZeneca, Alnylam Pharmaceuticals, Leerink Partners, Noble Insights, MedGenome, Aegerion Pharmaceuticals, Regeneron Pharmaceuticals, Quest Diagnostics, Color Genomics, Genomics PLC, and Eli Lilly and Company; and holds equity in San Therapeutics, Catabasis Pharmaceuticals, and Endcadia. No other potential conflicts of interest relevant to this article were reported.

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10.2337/db18-0857

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Emdin, C. A., Khera, A. V., Aragam, K., Haas, M., Chaffin, M., Klarin, D., Natarajan, P., Bick, A., Zekavat, S. M., Nomura, A., Ardissino, D., Wilson, J. G., Schunkert, H., McPherson, R., Watkins, H., Elosua, R., Bown, M. J., Samani, N. J., Baber, U., ... Kathiresan, S. (2019). DNA sequence variation in ACVR1C encoding the activin receptor-like kinase 7 influences body fat distribution and protects against type 2 diabetes. Diabetes, 68(1), 226-234. https://doi.org/10.2337/db18-0857

@article{d05be3d8aded406da40f4768c14dc9c0,

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

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 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.",

author = "Emdin, \{Connor A.\} and Khera, \{Amit V.\} and Krishna Aragam and Mary Haas and Mark Chaffin and Derek Klarin and Pradeep Natarajan and Alexander Bick and Zekavat, \{Seyedeh M.\} and Akihiro Nomura and Diego Ardissino and Wilson, \{James G.\} and Heribert Schunkert and Ruth McPherson and Hugh Watkins and Roberto Elosua and Bown, \{Matthew J.\} and Samani, \{Nilesh J.\} and Usman Baber and Jeanette Erdmann and Namrata Gupta and John Danesh and Danish Saleheen and Stacey Gabriel and Sekar Kathiresan",

year = "2019",

month = jan,

day = "1",

doi = "10.2337/db18-0857",

language = "English",

volume = "68",

pages = "226--234",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "1",

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Emdin, CA, Khera, AV, Aragam, K, Haas, M, Chaffin, M, Klarin, D, Natarajan, P, Bick, A, Zekavat, SM, Nomura, A, Ardissino, D, Wilson, JG, Schunkert, H, McPherson, R, Watkins, H, Elosua, R, Bown, MJ, Samani, NJ, Baber, U, Erdmann, J, Gupta, N, Danesh, J, Saleheen, D, Gabriel, S & Kathiresan, S 2019, 'DNA sequence variation in ACVR1C encoding the activin receptor-like kinase 7 influences body fat distribution and protects against type 2 diabetes', Diabetes, Jg. 68, Nr. 1, S. 226-234. https://doi.org/10.2337/db18-0857

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 - https://www.scopus.com/pages/publications/85058885742

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 -

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

Abstract

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