Basso Federica, Lowe Gordon D O, Rumley Ann, McMahon Alex D, Humphries Steve E
Centre for Cardiovascular Genetics, BHF Laboratories, Royal Free and University College London Medical School, London, UK.
Arterioscler Thromb Vasc Biol. 2002 Apr 1;22(4):599-604. doi: 10.1161/01.atv.0000013283.84306.1a.
Interleukin (IL)-6 plays an important role in the pathogenesis of coronary heart disease (CHD). Two functional polymorphisms in the IL-6 promoter have been identified (-174G>C and -572G>C), with both the rare alleles being associated with higher plasma levels of IL-6 after bypass surgery and one of them (-174G>C) associated with CHD risk. We have studied the contribution of these polymorphisms to CHD risk in the West of Scotland Coronary Prevention Study (WOSCOPS), a primary prevention trial that demonstrated the effectiveness of pravastatin in reducing morbidity and mortality from CHD. Four hundred ninety-eight cases (consisting of individuals experiencing a cardiovascular event during 4.8 years of follow-up) and 1109 controls (individuals matched for age and smoking habits) were genotyped. In the placebo group, there was no significant evidence of higher risk associated with the -174CC genotype compared with the GG+GC group. However, in the pravastatin-treated group, CC homozygotes had a significantly lower risk of CHD compared with the GG+GC placebo group (odds ratio 0.46, 95% CI 0.27 to 0.79), and this remained statistically significant after adjustment for classic risk factors. Compared with the GG+GC group, men with the CC genotype had modestly, but not significantly, higher baseline levels of IL-6, C-reactive protein, or fibrinogen but showed a significantly greater fall in LDL cholesterol with statin treatment (P=0.036). The -572G>C polymorphism was not significantly associated with any plasma trait or CHD risk. Thus, in subjects under pravastatin treatment, the -174CC genotype was associated with a lower risk of CHD. These results demonstrate the importance of the inflammatory system in determining the risk of CHD and support the nonlipid effect of statins on risk.
白细胞介素（IL）-6在冠心病（CHD）的发病机制中起重要作用。已在IL-6启动子中鉴定出两个功能性多态性位点（-174G>C和-572G>C），两个罕见等位基因均与搭桥手术后较高的IL-6血浆水平相关，其中一个（-174G>C）与冠心病风险相关。我们在苏格兰西部冠心病预防研究（WOSCOPS）中研究了这些多态性对冠心病风险的影响，该研究是一项一级预防试验，证明了普伐他汀在降低冠心病发病率和死亡率方面的有效性。对498例病例（包括在4.8年随访期间发生心血管事件的个体）和1109例对照（年龄和吸烟习惯匹配的个体）进行了基因分型。在安慰剂组中，与GG+GC组相比，没有显著证据表明-174CC基因型与更高的风险相关。然而，在普伐他汀治疗组中，与GG+GC安慰剂组相比，CC纯合子患冠心病的风险显著降低（优势比0.46，95%可信区间0.27至0.79），在调整经典风险因素后，这一结果仍具有统计学意义。与GG+GC组相比，CC基因型男性的IL-6、C反应蛋白或纤维蛋白原基线水平略高，但无显著差异，但他汀类药物治疗后LDL胆固醇水平下降显著（P=0.036）。-572G>C多态性与任何血浆特征或冠心病风险均无显著关联。因此，在接受普伐他汀治疗的受试者中，-174CC基因型与较低的冠心病风险相关。这些结果证明了炎症系统在确定冠心病风险中的重要性，并支持他汀类药物对风险的非脂质效应。
