Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery
Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery
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DOI：
10.1161/circulationaha.105.001032
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发表时间：
2006-07-04
期刊：
影响因子：
37.8
通讯作者：
Schwinn, DA
中科院分区：
文献类型：
--
作者：
Podgoreanu, MV;White, WD;Schwinn, DA
背景：心脏手术合并体外循环（CPB）引发的炎症反应是术后心肌梗死（PMI）发病的主要机制，这是一种多因素疾病，具有显著的患者间变异性，临床和手术因素难以预测。我们检验了炎症通路中候选基因多态性与心脏手术后PMI风险相关的假设。方法和结果：我们对434例选择性心脏手术合并CPB患者的23个候选基因的48个多态性进行了基因分型。PMI定义为术后24小时肌酸激酶- mb同工酶水平>= 10 ×正常上限。采用两步分析策略：选择标记，然后建立模型。为了最大限度地减少假阳性关联，我们通过排列分析、Bonferroni校正和控制错误发现率来调整多重检测；52例（12%）出现PMI。经多重比较及临床危险因素调整后，发现3个多态性是PMI的独立预测因子（调整后P < 0.05，假发现率< 10%）。这些基因变体编码促炎细胞因子白细胞介素6 （IL6 -572G > C，比值比[OR]， 2.47）和2个粘附分子：细胞间粘附分子-1 （ICAM1 Lys469Glu， OR, 1.88）和e-选择素（SELE 98G > T， OR, 0.16）。纳入这些多态性的基因型信息改进了仅基于传统危险因素的PMI预测模型（c统计量为0.764对0.703）。结论：细胞因子和白细胞内皮相互作用途径的功能遗传变异与心脏手术后肌坏死的严重程度独立相关。这可能有助于术前高危心脏手术患者的识别和新的心脏保护策略的发展。
Background-The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery.Methods and Results-We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level >= 10 x upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted P < 0.05; false discovery rate < 10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 -572G > C; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98G > T; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703).Conclusions-Functional genetic variants in cytokine and leukocyte-endothelial interaction pathways are independently associated with severity of myonecrosis after cardiac surgery. This may aid in preoperative identification of high-risk cardiac surgical patients and development of novel cardioprotective strategies.