慢性阻塞性肺疾病合并肺动脉高压患者内皮型一氧化氮合酶基因多态性分析

Gene polymorphism of the endothelial nitric oxide synthase enzyme and pulmonary hypertension in patient with chronic obstructive pulmonary disease

目的 探讨内皮型一氧化氮合酶（eNOS）基因G894T多态性与COPD合并肺动脉高压（PAH）发病的相关性及可能机制。方法2005年1月至12月包头医学院第二附属医院就诊的50例COPD合并PAH患者，男31例，女19例，平均年龄（69±10）岁。健康对照组50名，男29名，女21名，平均年龄（67±3）岁。对两组的基因多态性特征进行研究。检测一氧化氮代谢物（NOx）及内皮素含量，应用特异性PCR比较eNOS基因G894T多态性的分布差异，分析基因型与COPD合并PAH患者发病的相关性。基因型、等位基因频率和组间计数资料比较采用X^2检验，组间均数比较采用t检验，相关性分析采用logistic回归进行统计学分析，数据均采用均数±标准差表示。结果COPD合并PAH组的GT、TT基因型频率及T等位基因频率均高于健康对照组；GT＋TT基因型组空腹血清NOx含量为（48±8）μmol／L，NOx与内皮素比值为0．51±0．20；GG基因型组NOx含量为（60±24）μmol／L，NOx与内皮素比值为1．43±0．64；GT＋TT基因型组内皮素含量为（104±38μg/L，明显高于GG基因型组的（50±26）μg／L；GG基因型组肺动脉压[（47±10）mm Hg，1 mm Hg=0．133kPa]明显低于GT＋TT基因型组的（57±15）mm Hg；GT＋TT基因型组右心室游离壁厚度为（4，32±1．06）mm，GG基因型组为（3．84±0．56）mm。GG基因型组与GT＋TT基因型组比较其他心脏结构无差异。所有患者二尖瓣血流早期与晚期充盈速度比值均〈1，而左心室横径短轴缩短分数与射血分数均正常，存在左心室舒张功能障碍，而收缩功能正常。回归分析结果显示，eNOS基因G894T多态性的T等位基因（P〈0．01，OR值为17．24，95％可信区间为4．19～72．48）、一氧化氮（P〈0．01，OR值为0．97，95％可信区间为0．95～0．99）及吸烟（P〈0.01，OR值为9．45，95％可信区间为2．94～30．38）与COPD合并PAH明显相关。结论 eNOS基因G894T多态性可能与COPD合并PAH的发生有关，eNOS基因可能是COPD合并PAH的候选基因。

Objective To investigate the relationship between the gene polymorphism of the endothelial nitric oxide synthase enzmye （eNOSG894T） with pulomonary hypertension of Chinese patient with chronic obstructive pulmonary disease （COPD）. Methods Fifty normal volunteers （29 male, 21 female, mean age 67 ± 3 ） and 50 patients with COPD complicated by pulmonary hypertension （31 male, 19 female, mean age 69 ± 10） were included in the study. Lung function, arterial blood gases, and echocardiographic examination were performed. The genotype of eNOSG894T was determined with PCR. Results The frequencies of GT ＋ TT genotype and T allele were significantly greater in the patients compared to the controls. The levels of NOx and NOx/ET were lower in the GT ＋ TT genotype [ （48 ± 8 ） μmol/L, （0. 51±0. 20） ] than in the GG genotype [ （60 ± 24） μmol/L, （ 1.43 ± 0. 64） ] of COPD. The level of ET was higher in the GT ＋ TT genotype [ （ 104 ±38 μg/L] than in the GG genotvpe [ （ 50±26μg/L] of COPD patients. The mean systolic pulmonary artery pressure was higher in the GT ＋ TT genotype [（57±15） mm Hg, 1 mm Hg =0. 133 kPa] than in the GG genotype [（47 ±10） mm Hg] of COPD patients. In stepwise logistic regression analysis for predicting pulmonary artery pressure, the polymorphism of eNOS gene, the level of Nox and smoking were found to be independent variables. Conclusion The G894T polymorphism of eNOS gene is associated with pulmonary hypertension of COPD in a Chinese population. T allele may be involved in the etiology of pulmonary hypertension with COPD by reducing NO release of the endothelium.