Supplementary Material for: Dimethylarginine Dimethylaminohydrolase 1 Polymorphisms and Venous Intimal Hyperplasia in Hemodialysis Patients

Background: After angioplasty, veins are more prone to intimal hyperplasia than arteries. Veins tend to produce less nitric oxide (NO), which could lead to endothelial dysfunction. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase and contributes to cardiovascular disease. In humans, dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme for ADMA degradation. In this study, we aim to determine whether venous intimal hyperplasia in hemodialysis (HD) vascular access is influenced by common polymorphisms in the DDAH1 genes. Methods: This is a prospective observational cohort study. A total of 473 HD patients referred for the angioplasty of vascular access were enrolled. There were 190 arteriovenous grafts (AVG) and 283 arteriovenous fistulas (AVF). The follow-up lasted for 2 years after the interventions. Seven single nucleotide polymorphisms (SNPs) in DDAH1 were genotyped and ADMA were measured at baseline. The primary outcome was restenosis after angioplasty. Results: Among the 7 SNPs, plasma ADMA levels were significantly different in DDAH1 rs233112 (GA + GG vs. AA, 0.86 ± 0.23 vs. 0.82 ± 0.19 μM, p = 0.03) and rs1498373 (CT + TT vs. CC, 0.87 ± 0.23 vs. 0.82 ± 0.20 μM, p = 0.02) genotypes. The AVF group with GG + GA genotype of rs233112 and CT + TT genotype of rs1498373 had higher risks of early restenosis at 3 months. In the AVG group, only GG + GA genotype of rs233112 was associated with early restenosis. A combined analysis of AVG and AVF groups showed that patients with rs233112 GA + GG genotype and rs1498373 CT + TT genotype had higher risks of early restenosis (both p Conclusions: Our findings suggest that certain DDAH1 polymorphisms modulate circulating ADMA levels and are associated with venous intimal hyperplasia.背景：经皮血管成形术（angioplasty）后，静脉相较于动脉更易发生内膜增生。静脉生成的一氧化氮（nitric oxide，NO）水平通常更低，这可能引发内皮功能障碍（endothelial dysfunction）。不对称二甲基精氨酸（asymmetric dimethylarginine，ADMA）是一氧化氮合酶（nitric oxide synthase）的内源性抑制剂，与心血管疾病的发生发展密切相关。在人体中，二甲基精氨酸二甲基氨基水解酶1（dimethylarginine dimethylaminohydrolase 1，DDAH1）是降解ADMA的主要酶类。本研究旨在探讨血液透析（hemodialysis，HD）血管通路相关静脉内膜增生是否受DDAH1基因常见多态性的影响。 方法：本研究为前瞻性观察队列研究。共纳入473例因血管通路需行血管成形术的血液透析患者，其中包括190例动静脉移植物（arteriovenous graft，AVG）患者与283例动静脉内瘘（arteriovenous fistula，AVF）患者。干预后随访时长为2年。对DDAH1基因的7个单核苷酸多态性（single nucleotide polymorphism，SNP）位点进行基因分型，并于基线水平检测血浆ADMA水平。本研究的主要结局为血管成形术后再狭窄（restenosis）。 结果：在7个SNP位点中，DDAH1基因rs233112位点（GA+GG基因型 vs AA基因型：0.86±0.23 vs 0.82±0.19 μM，p=0.03）与rs1498373位点（CT+TT基因型 vs CC基因型：0.87±0.23 vs 0.82±0.20 μM，p=0.02）的血浆ADMA水平存在显著差异。携带rs233112位点GG+GA基因型与rs1498373位点CT+TT基因型的AVF患者，术后3个月早期再狭窄风险更高。在AVG患者亚组中，仅rs233112位点GG+GA基因型与早期再狭窄相关。对AVF与AVG患者进行合并分析显示，携带rs233112 GA+GG基因型及rs1498373 CT+TT基因型的患者早期再狭窄风险更高（两者的p值均[原文未完整标注]）。 结论：本研究结果表明，特定的DDAH1基因多态性可调节循环ADMA水平，并与静脉内膜增生相关。