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DOI: 10.2337/db06-1421
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Original Research |
Evidence that Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) on 1q21 is a type 2 diabetes susceptibility gene in the Old Order Amish
1Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201
2Diabetes Molecular Genetics Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, DHHS, Phoenix, AZ 85004
3Geriatric Research and Education Clinical Center (GRECC), Veterans Administration Medical Center, Baltimore, MD 21201
Correspondence: Ashudin{at}medicine.umaryland.edu
Rho guanine nucleotide exchange factor 11 (ARHGEF11), located on chromosome 1q21, is involved in G protein signaling, a pathway known to play a role in both insulin secretion and action. We genotyped 52 SNPs in ARHGEF11 and compared genotype frequencies between subjects with T2D (n = 145), or T2D and impaired glucose tolerance (T2D/IGT) (n = 293), versus normal glucose tolerance (NGT) controls (n = 358). Thirty SNPs, spanning the entire gene, were significantly associated with T2D or T2D/IGT. The most significantly associated SNP was rs6427340 (intron 2) in which the less common allele was the risk allele [odds ratio (95% CI) = 1.82 (1.20 -- 2.70), p = 0.005 for T2D vs. NGT and 1.79 (1.27 -- 2.50), p = 0.0008 for T2D/IGT vs. NGT]. In an expanded set of nondiabetic subjects (n = 754), most of the T2D/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 T2D/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 T2D.
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