Brull D J, Montgomery H E, Sanders J, Dhamrait S, Luong L, Rumley A, Lowe G D, Humphries S E
Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College London Medical School, London, UK.
Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1458-63. doi: 10.1161/hq0901.094280.
Interleukin-6 (IL-6) synthesized in response to diverse stimuli may play an important role in bridging the inflammatory and atherosclerotic processes. The acute-phase response after coronary artery bypass graft surgery (CABG) is associated with the induction and release of cytokines, such as IL-6. We have examined the effect of common polymorphisms in the IL-6 gene promoter (-174G>C, -572G>C, and -597G>A) on IL-6 levels after elective CABG. DNA extracted from the peripheral blood of 127 patients was amplified by polymerase chain reaction. IL-6 genotypes were resolved by gel electrophoresis after restriction enzyme digestion. Serum IL-6 was measured before surgery and in serial samples at 6, 24, 48, and 72 hours after CABG. Genotype distribution was as expected for a population in Hardy-Weinberg equilibrium for all polymorphisms. Rare allele frequencies (+/-95% CIs) were similar to those reported previously: -597A 0.36 (0.30 to 0.42), -572C 0.07 (0.04 to 0.10), and -174C 0.37 (0.31 to 0.43). The -174G>C and -597G>A genotypes were in strong allelic association (Delta=0.97, P<0.001). Baseline IL-6 levels did not significantly differ between patients with different genotypes for any polymorphism. However, 6 hours after CABG, peak IL-6 levels were significantly higher (P=0.03) in carriers of the -572C allele than in those of the -572GG genotype (355+/-67 versus 216+/-13 pg/mL, respectively) and in those with genotype -174CC compared with -174G allele carriers (287+/-31 versus 227+/-15 pg/mL, respectively; P=0.04). These effects remained statistically significant after adjusting for possible confounders, including age, sex, smoking, duration of cardiopulmonary bypass, aortic cross-clamp time, and total duration of surgery. These data demonstrate that IL-6 promoter polymorphisms influence peak IL-6 production after CABG, suggesting that these polymorphisms, which are functional in vitro, are also functional in vivo, suggesting a genetic influence on IL-6 levels after acute severe injury.
响应多种刺激而合成的白细胞介素-6（IL-6）可能在连接炎症和动脉粥样硬化过程中发挥重要作用。冠状动脉旁路移植术（CABG）后的急性期反应与细胞因子如IL-6的诱导和释放有关。我们研究了IL-6基因启动子中的常见多态性（-174G>C、-572G>C和-597G>A）对择期CABG后IL-6水平的影响。通过聚合酶链反应扩增从127例患者外周血中提取的DNA。经限制性内切酶消化后，通过凝胶电泳解析IL-6基因型。在手术前以及CABG后6、24、48和72小时采集的系列样本中检测血清IL-6。所有多态性的基因型分布均符合Hardy-Weinberg平衡群体的预期。罕见等位基因频率（±95%可信区间）与先前报道的相似：-597A为0.36（0.30至0.42），-572C为0.07（0.04至0.10），-174C为0.37（0.31至0.43）。-174G>C和-597G>A基因型存在强等位基因关联（Δ=0.97，P<0.001）。对于任何多态性，不同基因型患者的基线IL-6水平均无显著差异。然而，CABG后6小时，-572C等位基因携带者的IL-6峰值水平显著高于-572GG基因型携带者（分别为355±67与216±13 pg/mL，P=0.03），-174CC基因型患者的IL-6峰值水平高于-174G等位基因携带者（分别为287±31与227±15 pg/mL，P=0.04）。在对包括年龄、性别、吸烟、体外循环时间、主动脉阻断时间和手术总时长等可能的混杂因素进行校正后，这些效应仍具有统计学意义。这些数据表明，IL-6启动子多态性影响CABG后IL-6的峰值产生，提示这些在体外具有功能的多态性在体内也具有功能，表明急性严重损伤后IL-6水平受遗传因素影响。
