雄激素受体基因CAG重复数多态性与老年男性冠心病的关系及可能机制

Role of androgen receptor CAG repeat polymorphism in pathogenesis of coronary artery disease in elderlymen

目的探讨雄激素受体基因CAG重复数多态性对老年男性冠心病发病风险的影响及可能机制。方法选择296例有冠状动脉造影证据的老年男性，检测血清中游离睾酮（FT）和总睾酮（TT）水平，流式细胞术检测外周血淋巴细胞雄激素受体（AR）表达水平，并提取全血基因组DNA，通过聚合酶链反应扩增AR基因片段（含CAG重复数多态性位点），所得产物经微卫星扫描分析和基因分型，最终得到相应的ARCAG重复数。结果老年男性患者的ARCAG重复数波动在11-28（P25-P75：18-22；中位数为20），以P，5％为界分为长AR组[（CAG）n≥22，82例]和短AR组（CAG）n〈22，214例]。两组比较，短AR组的FT水平低于长AR组（24．1±23．1）×10^-6mmol／L与（31．2±27．8）×10^-6mmol／L（P〈0．05），短AR组合并冠心病者FT水平低于对照组（22．4±20．5）×10^-6mmol／L与（33．6±32．4）×10^-6mmol／L（P〈0．01）；而短AR组冠心病发病率84．1％（180例）高于长AR组69．5％（57例）（P〈0．01）。长AR组与短AR组的TT水平和淋巴细胞AR表达水平差异无统计学意义。未发现AR基因（CAG）n重复数多态性对雄激素水平及淋巴细胞表达水平有影响，年龄是FT和AR水平的主要影响因素。Logistic回归分析结果显示，FT水平与冠心病风险呈负相关（OR=0．98，95％CI：0．973-0．998，P=0．01），短AR增加冠心病发病风险（OR=3．44，95％CI：1．887-6．264，P〈0．01）。结论在老年男性中，雄激素受体CAG重复数短者，年龄相关的雄激素（主要是FT）水平下降更显著，与冠心病发病风险增加有关。

Objective To investigate the relationship of androgen receptor （AR） CAG repeat polymorphism and coronary artery disease （CAD） in elderly men and its potential mechanism. Methods Totally 296 elderly men undergoing coronary angiography were enrolled in this study. Serum total testosterone （TT） and free testosterone （FT） levels were measured. Androgen receptors （ARs） in peripheral lymphocytes were determined by flow cytometry. Genome DNA was extracted from peripheral leucocytes using standard techniques. Gene fragments containing AR CAG repeats were amplified by PCR with specific fluorescent labeled primers. PCR products were separated with agarose gels. CAG repeat number of each sample was obtained by genotyping. Results AR CAG repeats varied from 11 to 28 （P25-P75 ： 18-22; median： 20） in elderly male patients. They were divided into the long AR group （CAG repeats≥22, n=82） and the short AR group （CAG repeats〈22, n= 214）. Compared with the long AR group, serum FT level was much lower in the short AR group （（24. 1±23.1） ×10^-6 mmol/L vs. （31.2±27.8） ×10^-6 mmol/L, P〈0.05）. The prevalence of coronary artery disease was higher in the short AR group than in the long AR group （84.1% （180 cases） vs. 69.5%（57 cases）, P〈0.05]. The FT level was lower in the short AR group combined with CAD than in the control group [（22.4±20.5） ×10^-6mmol/L vs. （33.6±32.4） ×10^-6mmol/L,P〈0.01]. There were no significant differences in serum TT and AR levels between the long and short AR groups. No significant correlations were found in the AR CAG repeats polymorphism with FT, TT or AR levels. Age was the main risk factor for FT and AR levels. Logistic regression analysis showed that FT level was negatively correlated with CAD （OR=0.98,95 %CI：0. 973-0. 998, P=0.01） ,and short AR increased the risk of CAD in elderly male patients （OR= 3.44,95% CI： 1. 887 6. 264,P〈0.01）. Conclusions Serum FT level is correlated with age and is significantly decreased in elderly male patients with short AR repeats, which may increase the risk of CAD in elderly men.