Genetic Determinants of Hypertensive Heart Disease in CRI

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DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chromic renal insufficiency (CRI). CVD remains the leading cause of death in dialysis patients and in patients undergoing renal transplantation. There is accumulating evidence that the increase in CVD burden is present in the pre-dialysis population. Left-ventricular hypertrophy (LVH) is perhaps the best studied marker of CVD in the chronic kidney disease (CKD) population. In all stages of kidney disease, LVH is predictive of increased cardiovascular morbidity and mortality and the prevalence of LVH increases at each stage of CKD. Increases in left-ventricular mass (LV mass), also called concentric remodeling, identifies a pre-dialysis patients with CRI at high risk for cardiovascular disease. The natriuretic peptide system (NPS) opposes the development of cardiac hypertrophy and fibrosis and is activated in CRI. The NPS describes the ability of the heart to synthesis and release of natriuretic peptides (atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], and C-type natriuretic peptide [CNP]) in response to pressure or volume overload. ANP, BNP and CNP exert systemic actions that include vasodilation, natriuresis and reduced activation of the renin-angiotenin- aldosterone system. In addition, the NPS functions as an autocrine and paracrine system that directly opposes cardiac hypertrophy and fibrosis. The central hypothesis of this project is that genetic variation in corin and related NPS pathway genes contributes to the progression of hypertensive heart disease in the setting of chronic renal insufficiency (CRI). The candidate genes of interest are: corin, furin, ANP, BNP, CNP, NPR-A, NPR-B, NPR-C, PKG-I, and NEP. We will test these hypotheses in the Chronic Renal Insufficiency Cohort (CRIC): an NIH-sponsored, multi-center, prospective cohort study of cardiovascular disease in subjects (N=3000) with chronic renal insufficiency. We will test the hypothesis that genetic variation in the corin gene is associated with increased concentric cardiac hypertrophy and impaired natriuretic peptide processing in CRI, test the hypothesis that genetic variation in NPS candidate genes related to corin are associated with concentric cardiac hypertrophy, consider epistatic interactions between these candidate genes, and finally, test the hypothesis that genetic variation in corin and related NPS candidate genes is associated with the development of systolic dysfunction and incident heart failure in CRI.