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Published online January 9, 2008
Diabetes 57:1057-1062, 2008
DOI: 10.2337/db07-0886
© 2008 by the American Diabetes Association
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Association of the Distal Region of the Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 Gene With Type 2 Diabetes in an African-American Population Enriched for Nephropathy

Keith L. Keene1, Josyf C. Mychaleckyj2,3, Shelly G. Smith1, Tennille S. Leak1, Peter S. Perlegas4, Carl D. Langefeld5, Barry I. Freedman6, Stephen S. Rich2,3,7, Donald W. Bowden1,4,6, and Michèle M. Sale1,2,6,7,8

1 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
2 Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
3 Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
4 Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
5 Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
6 Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
7 Department of Medicine, University of Virginia, Charlottesville, Virginia
8 Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia

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

Abbreviations: AIM, admixture informative marker; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; ESRD, end-stage renal disease; HWE, Hardy-Weinberg equilibrium; LD, linkage disequilibrium; MAP, minor allele frequency; SNP, single nucleotide polymorphism

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 {chi}2 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.


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Copyright © 2008 by the American Diabetes Association.