Department of Molecular and Internal Medicine , Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
BACKGROUND: Synthesis of nitric oxide by endothelial nitric oxide synthase (ENOS) plays a key role in the atherosclerotic process. Several polymorphisms of the gene encoding ENOS are now known and have been investigated with respect to their influence on cardiovascular disease risk in the general population. The authors prospectively investigated whether ENOS gene polymorphisms determined the risk of cardiovascular complications in a cohort of hemodialysis patients. METHODS: A total of 335 nondiabetic hemodialysis patients were genotyped for 3 ENOS polymorphisms (T-786-->C, intron 4, and Glu298Asp polymorphism) and were followed up prospectively for a mean of 44.2 +/- 9.0 months. The end-points of the study were major cardiac, cerebrovascular, or peripheral vascular events. RESULTS: Two ENOS polymorphisms were associated with cardiovascular events: a T to C substitution at position -786 of the promoter and a deletion-insertion in intron 4 (the a allele having 4 repeats of a consensus sequence and the b allele having 5 repeats). A total of 84 subjects were -786C carriers (CC+TC), and 15 (18%) suffered from cardiovascular events compared with only 13 of 251 TT patients (5%). The relative risk of cardiovascular events was higher for -786C carriers compared with noncarriers (relative risk: 2.05, P = 0.0003). It was also higher for a allele carriers (intron 4 polymorphism) compared with noncarriers (relative risk: 1.97, P = 0.0005). CONCLUSION: T-786-->C polymorphism and intron 4 polymorphism, but not Glu298Asp polymorphism, of the ENOS gene can influence the risk of cardiovascular events in Japanese nondiabetic hemodialysis patients.