Genetics of inflammation in post myocardial infarction heart failure

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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.