Length polymorphism in heme oxygenase-1 is associated with arteriovenous fistula patency in hemodialysis patients
Length polymorphism in heme oxygenase-1 is associated with arteriovenous fistula patency in hemodialysis patients
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DOI：
10.1038/sj.ki.5000019
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发表时间：
2006-01-01
影响因子：
19.6
通讯作者：
Chung, MY
中科院分区：
文献类型：
--
作者：
Lin, CC;Yang, WC;Chung, MY
血红素加氧酶-1（HO-1）是血红素降解的限速酶，产生一氧化碳（CO），在血管壁中具有有效的抗增殖和抗炎作用。HO-1基因的转录受启动子区二核苷酸鸟苷胸腺嘧啶重复序列（GT）（n）的长度多态性的调节，本研究测定了HO-1基因的转录与中国台湾血液透析（HD）患者动静脉瘘（AVF）失败的关系。L等位基因平均值（GT）（n）>= 30和S等位基因平均值（GT）（n）< 30。因此，L/L基因型有两个L等位基因，L/S基因型有一个L和一个S等位基因，S/S基因型有两个S等位基因。在入组本研究的603例HD患者中，178例患者有AVF失败史，425例患者无AVF失败史。AVF失败与以下因素之间存在显著相关性（风险比）：HD持续时间更长（1.004个月），泵流量较低（0.993 ml/min），较高的动态静脉压（1.010 mmHg），AVF位于右侧HO-1基因型为L/L和L/S（2.040 vs S/S）。AVF失败的比例从S/S型的20.3%和L/S型的31.0%增加到L/L型的35.4%（P = 0.011）。L/L、L/S和S/S基因型HD患者的相对发生率分别为1/87.6（1次发作/87.6患者月）、1/129和1/224.9（P < 0.002）。在S/S、L/S和L/L基因型中，5年时AVF的无辅助通畅率分别从83.8%（124/148）显著下降至75.1%（223/297）和69%（109/158）（P < 0.0001）。与S/S基因型HD患者相比，L/L基因型HD患者的冠状动脉疾病患病率更高（29.1vs14.2%; P = 0.005）。HO-1基因中（GT）（n）>= 30的较长长度多态性与血液透析患者中较高的入路失败率和较差的AVF通畅率相关。HO-1基因启动子中较长的GT重复序列可能抑制基因转录，从而抵消CO介导的抗血管损伤的保护作用。
Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme degradation, producing carbon monoxide ( CO), which carries potent antiproliferative and anti-inflammatory effects in the vascular walls. Transcription of the HO-1 gene is regulated by the length polymorphism of dinucleotide guanosine thymine repeat (GT)(n) in the promoter region, which was measured in this study to determine its association with arteriovenous fistula (AVF) failure in Chinese hemodialysis (HD) patients in Taiwan. L allele means (GT)(n) >= 30 and S allele means (GT)(n) < 30. Therefore, there are two L alleles for L/L genotype, one L and one S allele for L/S genotype, and two S alleles for S/S genotype. Among the 603 HD patients who were enrolled in this study, 178 patients had history of AVF failure, while 425 patients did not. Significant associations were found between AVF failure and the following factors ( hazard ratio): longer HD duration (1.004 month), lower pump flow (0.993 ml/min), higher dynamic venous pressure (1.010 mmHg), location of AVF on the right side (1.587 vs left side) and upper arm (2.242 vs forearm), and L/L and L/S genotypes of HO-1 (2.040 vs S/S genotype). The proportion of AVF failure increased from 20.3% in S/S genotype and 31.0% in L/S genotype to 35.4% in L/L genotype (P = 0.011). Relative incidences were 1/87.6 (1 episode per 87.6 patient-months), 1/129, and 1/224.9 for HD patients with L/L, L/S, and S/S genotypes, respectively (P < 0.002). The unassisted patency of AVF at 5 years decreased significantly from 83.8% (124/148) to 75.1% (223/297) and 69% (109/158) in S/S, L/S, and L/L genotypes, respectively (P < 0.0001). In comparison with HD patients with S/S genotype, those with L/L genotype had a higher prevalence of coronary artery disease (29.1 vs 14.2%; P = 0.005). A longer length polymorphism with (GT)(n) >= 30 in the HO-1 gene was associated with a higher frequency of access failure and a poorer patency of AVF in HD patients. The longer GT repeat in the HO-1 promoter might inhibit gene transcription, and consequently offset the CO-mediated protective effect against vascular injury.