Experimental studies have established that oxidative stress is a major determinant of LV remodeling, and as a result, contributes to the development of LV dysfunction. Myocardial redox status is determined by the balance between anti and prooxidant enzymes that are under genetic control. Single nucleotide polymorphisms (SNPs) have been identified in genes for several oxidant (antioxidants: superoxide dismutases, glutathione peroxidase, catalase, paraoxonase, heme oxygenase; prooxidants: myeloperoxidases, NAD(P)H oxidases) and nitrosant (nitric oxide synthases) pathway enzymes. Some of these have been associated with altered enzymatic activity/stability, which based upon animal studies could contribute to LV remodeling. It is unclear if SNPs in genes for these enzymes are associated with alterations in oxidative stress biomarkers, or with echocardiographic (echo) indices of LV remodeling (LV dilation or hypertrophy) in humans. As part of this response to the RFA, we will measure plasma total antioxidant status (TAS), protein carbonyls, myeloperoxidase, heat shock protein 70, and urinary 3-nitrotyrosine in 1563 Framingham Heart Study (FHS) subjects. We will use existing echo, urinary isoprostane data for these subjects, and will genotype for known missense and regulatory SNPs in the genes for oxidant pathway enzymes as part of the FHS component of the NHLBI Program for Genomic Applications. We hypothesize that SNPs associated with decreased antioxidant or increased prooxidant activity will be associated with increased systemic levels of biomarkers of oxidative stress, reduced plasma TAS, and with increased LV internal dimensions and LV mass. We also postulate that biomarkers of oxidative stress will be positively associated with increased echo LV mass and internal dimensions. These hypotheses will be addressed in 3 Specific Aims: 1. Examine the relations of SNPs in oxidative pathway enzyme genes and biomarkers of oxidative stress 2. Analyze the cross-sectional relations between oxidative stress biomarkers and echo LV dimensions and LV mass. 3. Investigate the cross-sectional relations of SNPs in oxidative pathway enzyme genes to echo LV measurements. This proposal responds to the RFA by integrating genotypic and phenotypic characterization of oxidative stress, relating oxidative stress measures to echo indices of LV remodeling, using existing FHS data sets and stored biological specimens, and establishing a multidisciplinary collaboration of molecular biologists, scientists with expertise in evaluating oxidative stress, genetic and cardiovascular epidemiologists, and statisticians.
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