Mannose binding lectin and outcomes following CABG

描述(申请人提供)：冠状动脉血管疾病可导致心肌梗死。虽然护理标准的提高极大地改善了脑梗塞后的发病率和死亡率，但现在人们普遍认为，缺血/再灌注(I/R)损伤发生在成功的溶栓治疗、经皮冠状动脉腔内成形术和冠状动脉旁路移植术(CABG)和体外循环(CPB)之后。尽管I/R、炎症和凝血功能障碍是导致围手术期不良结局(如表型)的已知因素，但观察到的这些结局的严重程度在个体之间存在显著差异。一种可能的解释是调节不良围手术期结局的生物通路中的遗传变异。包括我们自己在内的几个研究小组最近的基础科学研究表明，补体在I/R损伤中起着重要作用。我们已经证明，抑制凝集素补体途径中甘露糖结合凝集素(MBL)依赖的部分在心肌缺血动物模型再灌注后的炎症、功能障碍和损伤中起重要作用。为了评估凝集素补体途径(LCP)在人类疾病中的作用，我们建立并验证了一种新的荧光连接免疫分析法(FLISA)，以检测凝集素补体途径的功能方面与人类血清中C3裂解水平的关系。CABG基因组计划的初步单倍型数据表明，高表达的MBL2“LYQA分泌物”单倍型是CABG手术后心肌梗死的独立预测因子。在目前的应用中，我们将通过使用CABG基因组计划数据库和样本库在CABG环境中结合基因组(MBL2)和表型(MBL浓度)数据来扩展我们的基础和临床科学发现。我们假设MBL2基因内的遗传变异和围术期血清MBL水平将是体外循环冠脉搭桥术后心肌损伤的预测指标。根据这一建议产生的数据不仅将进一步确定MBL和LCP在心肌损伤中的作用，而且还将提供对易导致心脏手术后围术期并发症的遗传和分子机制的洞察。此外，这些特定目标的成功完成可能随后导致围手术期风险分层、资源利用的改善，以及将用于资助的临床试验的新型抗补体疗法的开发。与公共健康相关：心血管疾病死亡仍然是美国人的头号杀手。最近的人类和动物研究结果表明，已知的天然免疫分子(如甘露糖结合凝集素，MBL2)的遗传变异性和该蛋白的血清浓度分别是冠状动脉旁路移植术(CABG)和心肌缺血/再灌注后心肌损伤的独立预测因子。使用我们实验室最近开发的一种新的、经过验证的免疫分析方法，我们将利用CABG基因组计划数据库和样本库，研究MBL2基因和围手术期MBL2血清浓度(及其下游激活产物C4b和C3b)的遗传变异，以预测CABG后发生的心肌损伤。

DESCRIPTION (provided by applicant): Coronary vascular disease can lead to myocardial infarction. While increased standards of care have greatly improved morbidity and mortality following infarction, it is now widely accepted that ischemia/reperfusion (I/R) injury occurs following successful thrombolytic therapy, percutaneous transluminal coronary angioplasty and coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Although I/R, inflammation and coagulation disturbances are known to contribute to perioperative adverse outcomes (e.g., the phenotypes), the observed severity of these outcomes differs significantly amongst individuals One possible explanation is genetic variability in the biologic pathways that mediate adverse perioperative outcomes. Recent basic science studies from several groups, including our own, have shown that complement plays an important role in I/R injury. We have shown that inhibition of the mannose-binding lectin (MBL)-dependent portion of the lectin complement pathway plays an important role in the inflammation, dysfunction and injury following reperfusion in animal models of myocardial ischemia. In order to evaluate the role of the lectin complement pathway (LCP) in human diseases, we developed and validated a novel fluorochrome-linked immunoassay (FLISA) to measure the functional aspects of the lectin complement pathway to the level of C3 cleavage in human sera. Preliminary haplotype data from the CABG Genomics Program demonstrate that the high expressor MBL2 "LYQA secretor" haplotype is an independent predictor of postoperative myocardial infarction following CABG surgery. In the present application, we will extend our basic and clinical science findings by combining genomic (MBL2) and phenotypic (MBL concentration) data in the setting of CABG using the CABG Genomic Program database and sample repository. We hypothesize that genetic variation within the MBL2 gene and perioperative serum MBL levels will be predictive indicators of myocardial injury after CABG surgery with CPB. Data generated from this proposal will not only further define the role of MBL and the LCP in myocardial injury, but will also provide insight into genetic and molecular mechanisms that predispose individuals to perioperative morbidity following cardiac surgery. Furthermore, successful completion of these specific aims may subsequently lead to improved perioperative risk stratification, resource utilization and the development of novel anti-complement therapies to be used in a funded clinical trial. PUBLIC HEALTH RELEVANCE: Death from cardiovascular disease remains the number one killer of Americans. Recent scientific findings from human and animal studies have demonstrated that genetic variability of a known innate immune molecule (e.g., mannose binding lectin, MBL2) and the serum concentration of this protein are independent predictors of myocardial injury following coronary artery bypass grafting (CABG) and myocardial ischemia/reperfusion, respectively. Using a novel and validated immunoassay that was recently developed in our laboratory, we will investigate the genetic variation within the MBL2 gene and perioperative MBL2 serum concentration (as well as its downstream activation products, C4b and C3b) in predicting the myocardial injury that occurs following CABG using the CABG Genomics Program database and sample repository.