Longer GT Repeat Polymorphism in Heme Oxygenase-1 Gene Promoter Is Associated with Peripheral Artery Obstructive Disease in Patients Receiving Hemodialysis

Abstract

BACKGROUND: Peripheral artery occlusive disease (PAOD) is prevalent in patients receiving hemodialysis (HD) and influences their mortality. However, few studies have identified PAOD risk factors among patients receiving HD. Heme oxygenase-1 (HO-1) has recently been found to be a risk factor for vascular disease and guanidinium thiocyanate (GT) repeat polymorphism in the HO-1 gene promoter has been shown to affect its activity. This study was initiated to evaluate the risk factors for PAOD and mortality in patients receiving HD, including potential associations with polymorphism in HO-1 gene promoter.METHODS: Data for this study were collected as part of a 1-year, prospective, multicenter, observational study. We enrolled 342 patients under regular dialysis from 7 HD centers in northern Taiwan. The ankle brachial pressure index (ABI) ＜ 0.9 indicated a diagnosis of PAOD. Clinical data were obtained from medical records. The (GT)n repeat length polymorphism in the HO-1 gene promoter was assayed according to the standard procedure. We defined (GT)n repeat length ＜ 28 as short repeat (S) and repeat length ≥ 28 as long repeat (L).RESULTS: One hundred and five patients (30.7%) were diagnosed with PAOD. Multivariate analysis revealed that old age (1.038 [1.016-1.060], P = 0.0005), diabetes (2.38 [1.425-3.984], P = 0.0009), and history of stroke (3.83 [1.577-9.346], P = 0.003) were independent risk factors for PAOD. In contrast, the incidence of history of hepatitis B (0.215 [0.068-0.675], P = 0.0084) and calcium (mg/dL) × phosphorous (mg/dL) product (Ca × IP) ＞ 60 (0.373 [0.149-0.931], P = 0.0345) were lower in PAOD patients. Compared with patients without PAOD (NPAOD) during the 1-year follow-up period, patients with PAOD had higher rates of mortality (17.27% vs. 2.16%, P ＜ 0.0001) and rehospitalization (25.45% vs. 12.12%, P = 0.0019). The average (GT)n repeat length ≥ 28 was more common in PAOD than in NPAOD patients (41.9% vs. 30.8%, P = 0.049). There were six independent risk factors of mortality, including old age (HR = 1.071 [1.019-1.126], P = 0.007), PAOD diagnosis (HR = 1.071 [1.019-1.126], P = 0.007), history of stroke (HR = 4.132 [1.443-11.765], P = 0.0082) and diabetes (HR = 4.444 [1.203-16.393], P = 0.0253), presence of HO-1 SL genotype (HR = 7.54 [1.578-36.036], P = 0.0114), and lower serum albumin level (HR = 16.129 [5.076-52.632], P ＜ 0.0001).CONCLUSIONS: PAOD diagnosed by the ABI test was an independent risk factor for mortality in HD patients, and the occurrence of PAOD in patients receiving HD was associated with the longer GT repeat polymorphism in the HO-1 gene promoter. Additionally, HO-1 SL genotype was associated with 1-year mortality. Further study is required to understand the mechanisms underlying the role of HO-1 in the development of PAOD in patients receiving HD.