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Association of the distal region of the Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) gene with type 2 diabetes in an African American population enriched for nephropathy

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

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 mellitus (T2DM) in African Americans (AA) 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 T2DM- end stage renal disease (ESRD).

Research Design and Methods: Forty-nine SNPs located in the coding and flanking regions of ENPP1 were genotyped in 577 AA individuals with T2DM-ESRD and 596 AA controls. Haplotypic association and genotypic association for the dominant, additive, and recessive models were tested by calculating a ² statistic and corresponding P value.

Results: Nine SNPs showed nominal evidence for association (P< 0.05) with T2DM-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' UTR, 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 T2DM-ESRD in this AA population.

Conclusion: This study was the first to comprehensively evaluate variants of the ENPP1 gene for association in an AA population with T2DM and ESRD and suggests that variants in the distal region of the ENPP1 gene may contribute to diabetes or diabetic nephropathy susceptibility in AA.

Key Words: African American(s) • Association • Gene • Type 2 Diabetes

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