Investigation of the Estrogen Receptor-α Gene With Type 2 Diabetes and/or Nephropathy in African-American and European-American Populations

  1. Carla J. Gallagher12,
  2. Keith L. Keene1,
  3. Josyf C. Mychaleckyj134,
  4. Carl D. Langefeld3,
  5. Joel N. Hirschhorn56,
  6. Brian E. Henderson7,
  7. Candace J. Gordon1,
  8. Barry I. Freedman4,
  9. Stephen S. Rich3,
  10. Donald W. Bowden124 and
  11. Michèle M. Sale14
  1. 1Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
  2. 2Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
  3. 3Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
  4. 4Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
  5. 5Departments of Genetics and Pediatrics, Harvard Medical School, Boston, Massachusetts
  6. 6Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
  7. 7Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
  1. Address correspondence and reprint requests to Michèle M. Sale, PhD, Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. E-mail: msale{at}wfubmc.edu

Abstract

The estrogen receptor-α gene (ESR1) was selected as a positional candidate under a type 2 diabetes linkage peak at 6q24-27. A total of 42 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 380 African-American type 2 diabetic case subjects with end-stage renal disease (ESRD) and 276 African-American control subjects. A total of 22 ancestry informative markers were also genotyped, and the program Admixmap was used to adjust allelic and haplotypic association tests for individual estimates of admixture. The most significant association with type 2 diabetes–ESRD was with rs1033182 in intron 2 (P = 0.013, admixture-adjusted Pa = 0.021). Genotyping 17 SNPs across a region of ESR1 intron 1–intron 2 in an expanded population of 851 case and 635 control subjects supported association with rs1033182 (P = 0.004, Pa = 0.027) and with an independent six-SNP haplotype of high linkage disequilibrium spanning 6.4 kb (P < 0.0001, Pa < 0.0001). The same 17 ESR1 SNPs were genotyped in 300 European-American type 2 diabetes–ESRD case subjects and 310 European-American control subjects. Two intron 2 SNPs, rs2431260 (P = 0.015) and rs1709183 (P = 0.019), and a four-SNP haplotype containing these SNPs (P = 0.033) were associated with type 2 diabetes and/or ESRD. Results suggest that intron 1 and intron 2 of the ESR1 gene may contain functionally important regions related to type 2 diabetes or ESRD risk.

Footnotes

  • C.J.G. and K.L.K. contributed equally to this work.

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-0303.

  • 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 December 18, 2006.
    • Received March 3, 2006.
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  1. doi: 10.2337/db06-0303 Diabetes March 2007 vol. 56 no. 3 675-684
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