Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism

Background. Polymorphisms in the endothelial nitric oxide synthase gene (eN OS) may be implicated in the development of nephropathy in patients with ty pe 1 or insulin-dependent diabetes mellitus (IDDM). Methods. Three groups of IDDM patients were selected to study this hypothes is: cases with advanced diabetic nephropathy (N = 78), cases with overt pro teinuria but normal serum creatinine (N = 74), and controls with normoalbum inuria despite 15 years of diabetes (N = 195). Parents of 132 cases and 53 controls were also examined and were used for the transmission disequilibri um test, a family-based study design to test association. Results. We examined four eNOS polymorphisms, and two were associated with diabetic nephropathy in the case-control comparisons: a T to C substitution in the promoter at position -786 and the a-deletion/b-insertion in intron 4. For the former, the risk of developing advanced nephropathy was higher f or C allele homozygotes than for the other two genotypes (odds ratio 2.8, 9 5% CI, 1.4 to 5.6). For the latter polymorphism, it was the a-deletion carr iers that had the higher risk (odds ratio 2.3, 95% CI, 1.3 to 4.0) in compa rison with noncarriers. Both polymorphisms were analyzed together as haplot ypes in a family-based study using the transmission disequilibrium test. Th e C/a-deletion haplotype was transmitted from heterozygous parents to cases with advanced diabetic nephropathy with a significantly higher frequency t han expected (P = 0.004). Conclusion. The findings of the case-control and family-based studies demon strate clearly that DNA sequence differences in eNOS influence the risk of advanced nephropathy in type 1 diabetes.