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
- 1Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
- 2Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
- 3Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
- 4Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
- 5Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
- 6Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina
- 7Department of Medicine, University of Virginia, Charlottesville, Virginia
- 8Department 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:
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.
- 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
- Received June 29, 2007.
- Accepted January 6, 2008.