Genetics of inflammation in post myocardial infarction heart failure

描述（申请人提供）：心力衰竭（HF）是一种流行性慢性疾病，严重影响患者的生命数量和质量。流行病学指标表明，心衰负担在老年人中下降得不成比例，导致重大的人力和社会成本。对这种与年龄有关的疾病的评估与美国国家老龄研究所的使命有关。心衰发生在心肌梗死（MI）后，由于炎症系统暴露于心肌坏死组织，这是一个强大的炎症刺激。因此，心肌梗死后HF是一种独特的临床实体，在缺血损伤和进行性左心室重构之前，由炎症反应促进，炎症反应部分由遗传决定。细胞因子（炎症反应的介质）和c反应蛋白（一种炎症标志物）与心肌梗死后HF的风险增加有关。在奥姆斯特德县心肌梗死队列中，临床特征预测心肌梗死后HF的能力有限。应用细胞因子通路和CRP基因的遗传关联来识别心肌梗死后HF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/细胞因子通路和CRP基因的单核苷酸多态性（snp）与心肌梗死后HF的关联。我们的假设是心肌梗死后HF部分是由基因决定的。特定的目的。在明尼苏达州奥姆斯特德县的心肌梗死队列中，测量选定细胞因子途径和CRP基因的遗传变异与心肌梗死后HF表型发展之间的关系。研究设计和方法。为了优化结果的普遍性，该研究将在以人群为基础的心肌梗死队列中进行。所有受试者将对细胞因子通路和CRP基因的snp进行基因分型。为了验证这一假设的具体目的，已招募了1994例心肌梗死病例，并提供了DNA样本进行基因分型。我们估计540名受试者将发展为心肌梗死后HF。HF表型将由Framingham标准[1]严格定义；逻辑回归将检验心肌梗死后HF与基因型之间的关系，并对传统危险因素进行调整。除了观察心肌梗死后HF与单个SNP或基因内单倍型的关系外，还将寻求潜在的基因-环境相互作用以及选定细胞因子途径和CRP多态性基因的相互作用。最后，将对基因型（与传统危险因素相比）对每个主要终点的相对贡献进行量化。

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.