Genetic Determinants of Hypertensive Heart Disease in CRI

描述(申请人提供)：心血管疾病(CVD)是慢性肾功能不全(CRI)患者发病率和死亡率的主要原因。心血管疾病仍然是透析患者和肾移植患者的主要死亡原因。越来越多的证据表明，心血管疾病负担的增加存在于透析前人群中。在慢性肾脏疾病(CKD)人群中，左心室肥厚(LVH)可能是研究最好的心血管疾病标记物。在肾脏疾病的所有阶段，左心室肥厚预示着心血管发病率和死亡率的增加，并且在慢性肾脏病的每个阶段左心室肥厚的患病率都增加。左心室质量(LV质量)的增加，也称为向心性重构，表明透析前CRI患者心血管疾病的风险较高。钠尿肽系统(NPS)可对抗心肌肥大和纤维化的发展，并在CRI中被激活。NPS描述了心脏在压力或容量超负荷时合成和释放利钠肽(心钠素[ANP]、脑利钠多肽[BNP]和C型利钠肽[CNP])的能力。ANP、BNP和CNP发挥全身作用，包括血管扩张、利钠和降低肾素-血管紧张素-醛固酮系统的激活。此外，NPS还起着自分泌和旁分泌系统的作用，直接对抗心肌肥大和纤维化。该项目的中心假设是，在慢性肾功能不全(CRI)的背景下，Corin和相关NPS途径基因的遗传变异有助于高血压心脏病的进展。候选基因有：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)中验证这些假设：这是一项由美国国立卫生研究院赞助的、多中心的前瞻性队列研究，研究对象为慢性肾功能不全受试者(N=3000)的心血管疾病。我们将检验Corin基因的遗传变异与CRI的向心性心肌肥厚增加和心钠素加工受损相关的假设，检验与Corin相关的NPS候选基因的遗传变异与向心性心肌肥厚相关的假设，考虑这些候选基因之间的上位性交互作用，最后检验Corin和相关NPS候选基因的遗传变异与CRI收缩功能障碍和心力衰竭的发展相关的假设。

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.