Association of the Distal Region of the Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 Gene With Type 2 Diabetes in an African-American Population Enriched for Nephropathy

  1. Michèle M. Sale1,2,6,7,8
  1. 1Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
  2. 2Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
  3. 3Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
  4. 4Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
  5. 5Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
  6. 6Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
  7. 7Department of Medicine, University of Virginia, Charlottesville, Virginia
  8. 8Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
  1. Address correspondence and reprint requests to Michele M. Sale, PhD, Center for Public Health Genomics, University of Virginia, P.O. Box 800717, Charlottesville, VA 22908. E-mail: msale{at}virginia.edu

Abstract

OBJECTIVE—Variants in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene have shown positive associations with diabetes and related phenotypes, including insulin resistance, metabolic syndrome, and type 1 diabetic nephropathy. Additionally, evidence for linkage for type 2 diabetes in African Americans was observed at 6q24-27, with the proximal edge of the peak encompassing the ENPP1 gene. Our objective was to comprehensively evaluate variants in ENPP1 for association with type 2 diabetic end-stage renal disease (ESRD).

RESEARCH DESIGN AND METHODS—Forty-nine single nucleotide polymorphisms (SNPs) located in the coding and flanking regions of ENPP1 were genotyped in 577 African-American individuals with type 2 diabetic ESRD and 596 African-American control subjects. Haplotypic association and genotypic association for the dominant, additive, and recessive models were tested by calculating a χ2 statistic and corresponding P value.

RESULTS—Nine SNPs showed nominal evidence for association (P < 0.05) with type 2 diabetic ESRD in one or more genotypic model. The most significant associations were observed with rs7754586 (P = 0.003 dominant model, P = 0.0005 additive, and P = 0.007 recessive), located in the 3′ untranslated region, and an intron 24 SNP (rs1974201: P = 0.004 dominant, P = 0.0005 additive, and P = 0.005 recessive). However, the extensively studied K121Q variant (rs1044498) did not reveal evidence for association with type 2 diabetic ESRD in this African-American population.

CONCLUSIONS—This study was the first to comprehensively evaluate variants of the ENPP1 gene for association in an African-American population with type 2 diabetes and ESRD and suggests that variants in the distal region of the ENPP1 gene may contribute to diabetes or diabetic nephropathy susceptibility in African Americans.

  • Received June 29, 2007.
  • Accepted January 6, 2008.
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  1. Diabetes vol. 57 no. 4 1057-1062
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