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Published online March 16, 2007
Diabetes 56:1363-1368, 2007
DOI: 10.2337/db06-1421
© 2007 by the American Diabetes Association
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Brief Report

Evidence That Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) on 1q21 is a Type 2 Diabetes Susceptibility Gene in the Old Order Amish

Mao Fu1, Mona M. Sabra1, Coleen Damcott1, Toni I. Pollin1, Lijun Ma2, Sandra Ott1, John C. Shelton1, Xiaolian Shi1, Laurie Reinhart1, Jeffrey O'Connell1, Braxton D. Mitchell1, Leslie J. Baier2, and Alan R. Shuldiner1,3

1 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland
2 Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Phoenix, Arizona
3 Geriatric Research and Education Clinical Center (GRECC), Veterans Administration Medical Center, Baltimore, Maryland

Address correspondence and reprint requests to Alan R. Shuldiner, MD, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 W. Redwood St., Room 494, Baltimore, MD 21201. E-mail: ashudin{at}medicine.umaryland.edu

Abbreviations: AUC, area under the curve; AFDS, Amish Family Diabetes Study; IGT, impaired glucose tolerance; LD, linkage disequilibrium; NGT, normal glucose tolerance; SNP, single nucleotide polymorphism

Rho guanine nucleotide exchange factor 11 (ARHGEF11), located on chromosome 1q21, is involved in G protein signaling and is a pathway known to play a role in both insulin secretion and action. We genotyped 52 single nucleotide polymorphims (SNPs) in ARHGEF11 and compared the genotype frequencies of subjects with type 2 diabetes (n = 145) or type 2 diabetes/impaired glucose tolerance (IGT) (n = 293) with those of control subjects with normal glucose tolerance (NGT) (n = 358). Thirty SNPs, spanning the entire gene, were significantly associated with type 2 diabetes or type 2 diabetes/IGT. The most significantly associated SNP was rs6427340 (intron 2), in which the less common allele was the risk allele (odds ratio [OR] 1.82 [95% CI 1.20–2.70], P = 0.005 for type 2 diabetes vs. NGT and 1.79 [1.27–2.50], P = 0.0008 for type 2 diabetes/IGT vs. NGT). In an expanded set of nondiabetic subjects (n = 754), most of the type 2 diabetes–and IGT-associated SNPs were significantly associated with glucose levels during an oral glucose tolerance test, with the same SNP (rs6427340) showing the most significant associations (P = 0.007). All type 2 diabetes–and IGT-associated SNPs were in high linkage disequilibrium and constitute a single 133-kb haplotype block. These results, coupled with similar findings in Pima Indians, suggest that sequence variation in ARHGEF11 may influence risk of type 2 diabetes.


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