收缩性心力衰竭中内皮型一氧化氮合酶基因的多态性：单倍型分析。
Polymorphisms of endothelial nitric oxide synthase gene in systolic heart failure: an haplotype analysis.
机构信息
Cardiovascular Experimental and Molecular Laboratory, The Heart Failure and Cardiac Transplant Unit, Cardiology Division at Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
出版信息
Nitric Oxide. 2012 Mar 31;26(3):141-7. doi: 10.1016/j.niox.2012.01.003. Epub 2012 Jan 21.
BACKGROUND
Endothelial nitric oxide synthase (eNOS) gene polymorphisms have been associated with the pathogenesis of cardiovascular diseases, but few studies have evaluated the role of eNOS haplotypes on the risk and prognosis of heart failure (HF). This prospective study was designed to analyze the impact of three eNOS polymorphisms (T-786C, VNTR4a/b and Glu298Asp) and their haplotypes on the susceptibility and clinical outcomes in HF outpatients with systolic dysfunction.
METHODS AND RESULTS
We conducted a case-control and a cohort study in which 316 HF patients and 360 healthy controls were recruited from a tertiary care university hospital. DNA was extracted from peripheral blood and eNOS polymorphisms were detected by PCR or PCR-RFLP. Patients were predominantly men, had a mean left ventricular ejection fraction of 31% and were followed-up for a median of 41months; there were 96 deaths, including 58 HF-related deaths. Genotype distribution of the eNOS T-786C, VNTR 4a/b and Glu298Asp was similar between HF patients and controls. Haplotype frequencies differed between HF patients and controls only in African-Brazilians (p=0.043). African-Brazilian patients that carried the haplotype -786C/4b/Asp298 had a better prognosis than patients that carried other haplotypes (log rank p value=0.016 for all-cause mortality). In a Cox proportional hazard model adjusted for clinical variables of risk, the -786C/4b/Asp298 haplotype remained as an independent genetic predictor of survival (adjusted HR=0.11; 95% CI=0.01-0.83; p=0.03).
CONCLUSIONS
The -786C/4b/Asp298 eNOS haplotype had a significant impact on HF susceptibility and prognosis, particularly in African-Brazilian patients.
背景
内皮型一氧化氮合酶（eNOS）基因多态性与心血管疾病的发病机制有关，但很少有研究评估 eNOS 单倍型对心力衰竭（HF）风险和预后的作用。本前瞻性研究旨在分析三个 eNOS 多态性（T-786C、VNTR4a/b 和 Glu298Asp）及其单倍型对伴有收缩功能障碍的 HF 门诊患者易感性和临床结局的影响。
方法和结果
我们进行了病例对照和队列研究，从一家三级护理大学医院招募了 316 名 HF 患者和 360 名健康对照者。从外周血中提取 DNA，通过 PCR 或 PCR-RFLP 检测 eNOS 多态性。患者主要为男性，平均左心室射血分数为 31%，中位随访时间为 41 个月；有 96 例死亡，包括 58 例 HF 相关死亡。HF 患者和对照组的 eNOS T-786C、VNTR4a/b 和 Glu298Asp 基因型分布相似。仅在非洲裔巴西人中，HF 患者和对照组的单倍型频率不同（p=0.043）。携带-786C/4b/Asp298 单倍型的非洲裔巴西裔患者的预后优于携带其他单倍型的患者（所有原因死亡率的对数秩检验 p 值=0.016）。在调整风险的临床变量的 Cox 比例风险模型中，-786C/4b/Asp298 单倍型仍然是生存的独立遗传预测因子（调整 HR=0.11；95%CI=0.01-0.83；p=0.03）。
结论
eNOS-786C/4b/Asp298 单倍型对 HF 的易感性和预后有显著影响，特别是在非洲裔巴西裔患者中。
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