Genetics of inflammation in post myocardial infarction heart failure

描述(申请人提供)：心力衰竭(HF)是一种流行比例的慢性疾病，严重损害受影响个人的生活质量和数量。流行病学指标表明，心力衰竭的负担在老年人中下降得不成比例，导致重大的人类和社会成本。对这种与年龄有关的疾病的评估与国家老龄研究所的使命相关。心力衰竭发生在心肌梗死(MI)后，由于炎症系统暴露在心肌坏死组织中，这是一种强烈的炎症刺激。因此，心梗后心力衰竭是一个独特的临床实体，在此之前会出现缺血性损伤和进行性的左心室重构，而炎症反应在一定程度上是由遗传因素决定的。炎症反应的中介物细胞因子和炎症标志物C反应蛋白(CRP)与心梗后心力衰竭的风险增加有关。在奥姆斯特县心梗队列中，临床特征预测心梗后心力衰竭的能力有限。细胞因子途径和C反应蛋白基因的遗传关联可用于识别心肌梗塞后心力衰竭，这是一种新的、有前途的心肌梗死后风险分层方法。因此，我们建议测量候选基因/单核苷酸多态(SNPs)的细胞因子途径和C反应蛋白基因与心肌梗塞后心力衰竭的相关性。我们的假设是，心肌梗塞后心衰部分是由基因决定的。明确目标。在明尼苏达州奥姆斯特德县的心梗队列中，测量选定细胞因子途径和C反应蛋白基因的遗传变异与心梗后心衰表型发展的相关性。研究设计与方法。为了优化结果的概括性，这项研究将在基于人群的MI队列中进行。所有受试者都将接受细胞因子途径和CRP基因的SNPs基因分型。为了验证这一假设，我们招募了1,994名心肌梗塞患者，并提供了DNA样本进行基因分型。我们估计有540名受试者会发生心肌梗塞后心力衰竭。心力衰竭的表型将由Framingham标准严格定义[1]；Logistic回归分析将检验心梗后心力衰竭与基因型(S)之间的关系，并调整传统的危险因素。除了观察心肌梗死后心衰与单个SNP或基因内单倍型的关系外，还将寻找潜在的基因-环境相互作用以及选定的细胞因子途径和C反应蛋白多态的基因相互作用。最后，将量化基因型(与传统危险因素相比)对每个主要终点的相对贡献。

DESCRIPTION (provided by applicant): Heart failure (HF) is a chronic disease of epidemic proportion, which impairs gravely the quantity and quality of life of affected individuals. Epidemiological indicators demonstrate that the burden of HF falls disproportionately in the elderly, leading to major human and societal costs. The assessment of this age related disease is relevant to the mission of the National Institute of Aging. HF occurs post myocardial infarction (MI), due to the exposure of the inflammatory system to myocardial necrotic tissue which is a powerful stimulus for inflammation. Thus, post MI HF is a distinct clinical entity preceded by ischemic injury and progressive left ventricular remodeling, promoted by the inflammatory response which is in part genetically determined. Cytokines, the mediators of the inflammatory responses, and C-reactive protein (CRP), an inflammatory marker, have been associated with increased risk of post MI HF. In the Olmsted County MI cohort, the ability of clinical characteristics to predict post MI HF is limited. The applicability of genetic associations of cytokine pathways and the CRP genes to identify post MI HF is a new, promising approach to post-MI risk stratification. Accordingly, we propose to measure the association of candidate genes/single nucleotide polymorphisms (SNPs) of cytokine pathways and CRP genes with post MI HF. Our hypothesis is that post MI HF is, in part, genetically determined. Specific aim. To measure the association between genetic variations within selected cytokine pathways and CRP genes with the development of the phenotype post MI HF, in a MI cohort from Olmsted County, MN. Research design and methods. To optimize generalizibility of results, the study will be performed in a population-based MI cohort. All subjects will be genotyped for SNPs of cytokine pathways and CRP genes. To test the hypothesis for the specific aim, 1,994 MI cases have been recruited and DNA samples are available for genotyping. We estimate 540 subjects will develop post MI HF. The HF phenotype will be rigorously defined by Framingham criteria [1]; Logistic regression will examine the association between post MI HF and genotype(s) with adjustment for traditional risk factors. In addition to looking at associations of post MI HF with an individual SNP or intragene haplotype, potential gene- environmental interactions and interactions of genes of selected cytokine pathways and CRP polymorphisms will be sought. Finally, the relative contribution of genotype (compared to traditional risk factors) to each primary endpoint will be quantified.