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

  1. Mao Fu1,
  2. Mona M. Sabra1,
  3. Coleen Damcott1,
  4. Toni I. Pollin1,
  5. Lijun Ma2,
  6. Sandra Ott1,
  7. John C. Shelton1,
  8. Xiaolian Shi1,
  9. Laurie Reinhart1,
  10. Jeffrey O'Connell1,
  11. Braxton D. Mitchell1,
  12. Leslie J. Baier2 and
  13. Alan R. Shuldiner13
  1. 1Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland
  2. 2Diabetes 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. 3Geriatric Research and Education Clinical Center (GRECC), Veterans Administration Medical Center, Baltimore, Maryland
  1. 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

Abstract

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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 16 March 2007. DOI: 10.2337/db06-1421.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1421.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 16, 2007.
    • Received October 7, 2006.
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  1. Diabetes vol. 56 no. 5 1363-1368
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