Association analysis of 29,956 individuals confirms that a low- frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion

Hanieh Yaghootkar, Alena Stancáková, Rachel M. Freathy, Jagadish Vangipurapu, Michael N. Weedon, Weijia Xie, Andrew R. Wood, Ele Ferrannini, Andrea Mari, Susan M. Ring, Debbie A. Lawlor, George Davey Smith, Torben Jørgensen, Torben Hansen, Oluf Pedersen, Valgerdur Steinthorsdottir, Daniel F. Guobjartsson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Kari StefanssonAndrew T. Hattersley, Mark Walker, Andrew D. Morris, Mark I. Mccarthy, Colin N.A. Palmer, Markku Laakso, Timothy M. Frayling*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

A recent study identified a low-frequency variant at CCND2 associated with lower risk of type 2 diabetes, enhanced insulin response to a glucose challenge, higher height, and, paradoxically, higher BMI. We aimed to replicate the strength and effect size of these associations in independent samples and to assess the underlying mechanism. We genotyped the variant in 29,956 individuals and tested its association with type 2 diabetes and related traits. The low-frequency allele was associated with a lower risk of type 2 diabetes (OR 0.53; P = 2 3 10-13; 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log10; P = 2 3 10-11; n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log10; P = 5 3 10-3; n = 13,118) but not fasting proinsulin (β = 0.01 log10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (β = 1.38 cm; P = 6 3 10-9; n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m2; P = 0.02; n = 24,807), estimated in four population-based samples, was less than in the original publication where the effect estimate was biased by analyzing case subjects with type 2 diabetes and control subjects without diabetes separately. Our study establishes that a low-frequency allele in CCND2 halves the risk of type 2 diabetes primarily through enhanced insulin secretion.

Original languageEnglish
Pages (from-to)2279-2285
Number of pages7
JournalDiabetes
Volume64
Issue number6
DOIs
Publication statusPublished - Jun 2015

Bibliographical note

Funding Information:
H.Y. and T.M.F. are funded by the European Research Council award (323195 and SZ-50371). R.M.F. is a Sir Henry Wellcome Postdoctoral Fellow (Wellcome Trust grant 085541/Z/08/Z). D.A.L. is funded by SP/07 1008/ 24066. A.T.H. is a Wellcome Trust Senior Investigator and a National Institute of Health Research senior investigator. M.I.M. is a Wellcome Trust Senior Investigator (Wellcome Trust: 090532 and 098381; Medical Research Council [MRC]: G0601261.) The Wellcome Trust provides support for GoDARTS (awards 072960/ z/03/z and 099177/z12/z). METSIM was supported by grants from the Academy of Finland, University of Eastern Finland, and Sigrid Juselius Foundation

Funding Information:
Acknowledgments. The authors thank the European Research Council, Wellcome Trust, and University of Exeter Medical School. The authors are grateful to all the participants in GoDARTS, the general practitioners, the Scottish School of Primary Care for their help in recruiting the participants, and the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The authors acknowledge the support of the Health Informatics Centre, University of Dundee, for managing and supplying the anonymized data and NHS Tayside, the original data owner. The authors are extremely grateful to all the families who took part in ALSPAC, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. Funding. H.Y. and T.M.F. are funded by the European Research Council award (323195 and SZ-50371). R.M.F. is a Sir Henry Wellcome Postdoctoral Fellow (Wellcome Trust grant 085541/Z/08/Z). D.A.L. is funded by SP/07 1008/ 24066. A.T.H. is a Wellcome Trust Senior Investigator and a National Institute of Health Research senior investigator. M.I.M. is a Wellcome Trust Senior Investigator (Wellcome Trust: 090532 and 098381; Medical Research Council [MRC]: G0601261.) The Wellcome Trust provides support for GoDARTS (awards 072960/ z/03/z and 099177/z12/z). METSIM was supported by grants from the Academy of Finland, University of Eastern Finland, and Sigrid Juselius Foundation. The U.K. MRC and the Wellcome Trust (grant 092731) and the University of Bristol provide core support for ALSPAC. The Danish substudy was supported by research grants from the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku .dk); the Lundbeck Foundation (www.lucamp.org); the Danish Agency for Science, Technology and Innovation; the PhD School of Molecular Metabolism; University of Southern Denmark; and the Copenhagen Graduate School of Health and Medical Sciences. The Inter99 study was initiated by T.J. (principal investigator), K. Borch-Johnsen (co-principal investigator, Steno Diabetes Centre and Holbæk Hospital), H. Ibsen (Holbæk Hospital), and T.F. Thomsen (Research Centre for Prevention and Health, Glostrup, Denmark). The steering committee is comprised of the former two and C. Pisinger (Research Centre for Prevention and Health, Glostrup University Hospita)l. The Inter99 project was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augus-tinus Foundation, the Ib Henriksen Foundation, and the Becket Foundation. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript. Duality of Interest. The Inter99 project was also funded by Novo Nordisk. No other potential conflicts of interest relevant to this article were reported. Author Contributions. H.Y. and T.M.F. conceived and designed the study. H.Y. analyzed data. R.M.F., S.M.R., D.A.L., and G.D.S. (with ALSPAC); E.F., A.M., and M.W. (with RISC); T.J., T.H., and O.P. (with Inter99); A.D.M. and C.N.A.P. (with GoDARTS); and M.L. (with METSIM) performed genotyping and phenotyping. H.Y. (with RISC, GoDARTS, and ALSPAC), A.S., and J.V. (with METSIM) performed statistical analysis. R.M.F., D.F.G., G.T., U.T., M.I.M., C.N.A.P., and M.L. commented on the manuscript. A.S., R.M.F., J.V., M.N.W., W.X., A.R.W., E.F., A.M., S.M.R., D.A.L., G.D.S., T.J., T.H., O.P., V.S., D.F.G., G.T., U.T., K.S., A.T.H., M.W., A.D.M., M.I.M., C.N.A.P., and M.L. agreed with the manuscript results and conclusions. T.M.F. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Publisher Copyright:
© 2015 by the American Diabetes Association.

Fingerprint

Dive into the research topics of 'Association analysis of 29,956 individuals confirms that a low- frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion'. Together they form a unique fingerprint.

Cite this