Genetic Determinants of Hypertensive Heart Disease in CRI

描述（由申请方提供）：心血管疾病（CVD）是慢性肾功能不全（CRI）患者发病和死亡的主要原因。CVD仍然是透析患者和接受肾移植患者死亡的主要原因。越来越多的证据表明，透析前人群中存在CVD负担增加。左心室肥大（LVH）可能是慢性肾脏病（CKD）人群中研究最多的CVD标志物。在肾脏疾病的所有阶段，LVH可预测心血管发病率和死亡率的增加，并且LVH的患病率在CKD的每个阶段都增加。左心室质量（LV mass）增加，也称为向心性重构，可将透析前CRI患者确定为心血管疾病的高风险患者。利钠肽系统（natriuretic peptide system，NPK）对抗心肌肥厚和纤维化的发展，并在CRI中被激活。心钠素描述了心脏在压力或容量超负荷时合成和释放利钠肽（心房利钠肽[ANP]、脑利钠肽[BNP]和C型利钠肽[CNP]）的能力。ANP、BNP和CNP发挥全身作用，包括血管舒张、尿钠排泄和降低肾素-血管紧张素-醛固酮系统的活化。此外，心肌细胞作为一种自分泌和旁分泌系统发挥作用，直接对抗心脏肥大和纤维化。该项目的中心假设是，corin和相关的p53通路基因的遗传变异有助于慢性肾功能不全（CRI）背景下高血压性心脏病的进展。感兴趣的候选基因是：corin、furin、ANP、BNP、CNP、NPR-A、NPR-B、NPR-C、PKG-I和NEP。我们将在慢性肾功能不全队列（CRIC）中检验这些假设：这是一项由NIH申办的、多中心、前瞻性队列研究，研究对象为慢性肾功能不全受试者（N=3000）。我们将检验corin基因的遗传变异与向心性心肌肥大增加和CRI中利钠肽加工受损相关的假设，检验corin相关的非编码候选基因的遗传变异与向心性心肌肥大相关的假设，考虑这些候选基因之间的上位相互作用，最后，验证corin和相关的cirrhosis候选基因的遗传变异与CRI患者收缩功能障碍和心力衰竭的发生相关的假设。

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.