Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes

Lu Qi, Marilyn C. Cornelis, Peter Kraft, Kristopher J. Stanya, W. H Linda Kao, James S. Pankow, Josée Dupuis, Jose C. Florez, Caroline S. Fox, Guillaume Paré, Qi Sun, Cynthia J. Girman, Cathy C. Laurie, Daniel B. Mirel, Teri A. Manolio, Daniel I. Chasman, Eric Boerwinkle, Paul M. Ridker, David J. Hunter, James B. MeigsChih Hao Lee, Rob M. van Dam, Frank B. Hu

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

Abstract

To identify type 2 diabetes (T2D) susceptibility loci, we conducted genome-wide association (GWA) scans in nested case-control samples from two prospective cohort studies, including 2591 patients and 3052 controls of European ancestry. Validation was performed in 11 independent GWA studies of 10 870 cases and 73 735 controls. We identified significantly associated variants near RBMS1 and ITGB6 genes at 2q24, best-represented by SNP rs7593730 (combined OR = 0.90, 95% CI = 0.86-0.93; P = 3.7 × 10-1). The frequency of the risk-lowering allele T is 0.23. Variants in this region were nominally related to lower fasting glucose and HOMA-IR in the MAGIC consortium (P < 0.05). These data suggest that the 2q24 locus may influence the T2D risk by affecting glucose metabolism and insulin resistance.

Original languageEnglish (US)
Article numberddq156
Pages (from-to)2706-2715
Number of pages10
JournalHuman molecular genetics
Volume19
Issue number13
DOIs
StatePublished - Apr 23 2010

Bibliographical note

Funding Information:
The NHS/HPFS T2D GWAS (U01HG004399) is a component of a collaborative project that includes 13 other GWAS funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI) (U01HG004738, U01HG004422, U01HG004402, U01HG0047 29, U01HG004726, U01HG004735, U01HG004415, U01HG0 04436, U01HG004423, U01HG004728, RFAHG006033) with additional support from individual NIH (NIDCR: U01DE018 993, U01DE018903; NIAAA: U10AA008401, NIDA: P01CA 089392, R01DA013423; NCI: CA63464, CA54281, CA1367 92, Z01CP010200). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information.

Funding Information:
Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract ‘High throughput geno-typing for studying the genetic contributions to human disease’ (HHSN268200782096C). Additional funding for the current research was provided by the National Cancer Institute (NCI, P01CA087969, P01CA055075), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, R01DK058845). The WGHS is supported by HL043851 and HL69757 from the National Heart, Lung, and Blood Institute (NHLBI) and CA047988 from NCI, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. The ARIC Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367 and R01HL086694 and NIH contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. W.H.L.K. was supported by K01-DK067207. The FHS was partially supported by the NHLBI’s Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (contract no. N02-HL-6-4278), and the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. FHS was also supported by the NIDDK: R01DK078616 to J.B.M., J.D. and J.C.F.; NIDDK K24 DK080140 to J.B.M. and NIDDK Research Career Award K23 DK65978, a Massachusetts General Hospital Physician Scientist Development Award and a Doris Duke Charitable Foundation Clinical Scientist Development Award to J.C.F. L.Q. is supported by National Institutes of Health grants RO1 HL71981, American Heart Association Scientist Development Award and the Boston Obesity Nutrition Research Center (DK46200). M.C.C. is a recipient of a Canadian Institutes of Health Research Fellowship. C.H.L. is supported by the American Heart Association and NIH (R01DK075046). K.J.S. is supported by NIH Roadmap training grant R90DK071507.

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