Abstract
Venous intimal hyperplasia is more aggressive than arterial intimal hyperplasia after angioplasty. Veins tend to produce less nitric oxide, which could predispose to endothelial dysfunction. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and contributes to vascular disease. In human, dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme degrading ADMA. We aimed to determine whether venous intimal hyperplasia in dialysis vascular access is influenced by common polymorphisms in the DDAH1 genes. This is a prospective observational cohort study. A total of 473 hemodialysis patients referred for angioplasty of hemodialysis vascular accesses were enrolled. There were 190 grafts and 283 native fistulas. Follow-up lasted for two years after interventions. Seven single nucleotide polymorphisms in DDAH1 were genotyped and ADMA were measured at baseline. Primary outcome was restenosis after angioplasty. Among the seven single nucleotide polymorphisms, plasma ADMA levels were significantly different in DDAH1 rs233112 (GA+GG vs. AA, 0.86 ± 0.23 vs. 0.82 ± 0.19μM, P=0.03) and rs1498373 (CT+TT vs. CC, 0.87 ± 0.23 vs. 0.82 ± 0.20 μM, P=0.02) genotypes. The native-access group with GG+GA genotype of rs233112 and CT+TT genotype of rs1498373 had higher risks of early restenosis at 3 months. In graft-access groups, only GG+GA genotype of rs233112 was associated with early restenosis. Combined analysis of graft- and native- access groups showed that patients with rs233112 GA+GG genotype and rs1498373 CT+TT genotype had higher risks of early restenosis (both p <0.001). In the multivariate analysis, the association of these genotypes with early restenosis is independent of clinical, access or biochemical Our findings suggest that certain DDAH1 polymorphisms modulate circulating ADMA levels and are associated with venous intimal hyperplasia.
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