Association of the distal region of the ectonucleotide pyrophosphatase/phosphodiesterase 1 gene with type 2 diabetes in an African-American population enriched for nephropathy.

Abstract

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). 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. 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. 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.