Association of Arachidonate 12-Lipoxygenase Genotype Variation and Glycemic Control With Albuminuria in Type 2 Diabetes

Background: Glycemic exposure activates 12-lipoxygenase (12LO) expression and formation of arachidonic acid-derived products. These products can induce cell hypertrophy, cell proliferation, and extracellular matrix deposition, potentially leading to diabetic nephropathy. Study Design: Cross-sectional study. Settings & Participants: 955 European-American siblings from 369 Diabetes Heart Study families. Participants were categorized as nondiabetic, diabetic with hemoglobin A_1c level less than 6.5%, and diabetic with hemoglobin A_1c level greater than 6.5% (uncontrolled type 2 diabetes mellitus). Predictor: Four haplotype-tagging variants in the arachidonate 12LO gene (ALOX12), glycemic control, and other covariates. Outcomes & Measurements: Albuminuria measured by means of urinary albumin-creatinine ratio (ACR). Results: Median ACR was 11.9 mg/g (interquartile range, 5.6 to 39.1). The overall test of the Arg261Gln genotypic association with ACR was significant (P = 0.009). Compared with 261Arg allele carriers, adjusted mean ACR was 42% greater in the 189 carriers of two 261Gln alleles (95% confidence interval, 10 to 83; P = 0.007). This association was confined to the group with uncontrolled type 2 diabetes mellitus (N = 623) with the greatest ACRs (P < 0.001). Adjustments for additional determinants of ACR yielded similar results. Limitations: Urine ACR was measured in duplicate on only a single occasion. This study was limited to European Americans. Conclusions: Consistent with animal and cellular studies, these results provide additional evidence of the importance of the 12LO pathway in the pathogenesis of human diabetic nephropathy.