Genetic Determinants of Hypertensive Heart Disease in CRI

CRI 中高血压心脏病的遗传决定因素

• 批准号: 7667173
• 负责人: Daniel L Dries
• 金额: $ 77.05万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667173
• 关键词: African; Aldosterone; Alleles; Atrial Natriuretic Factor; Binding; Blood Pressure; Brain natriuretic peptide; C-Type Natriuretic Peptide; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell surface; Chronic Kidney Failure; Chronic Kidney Insufficiency; Cleaved cell; Cohort Studies; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Development; Dialysis patients; Dialysis procedure; Enzymes; Event; Fibrosis; Functional disorder; Genes; Genetic Determinism; Genetic Variation; Grant; Heart; Heart Hypertrophy; Heart failure; High Prevalence; Hormones; Hypertension; International; Kidney Diseases; Kidney Failure; Kidney Transplantation; Left Ventricular Hypertrophy; Left Ventricular Mass; Linkage Disequilibrium; Minor; Molecular Biology; Morbidity - disease rate; Natriuresis; Natriuretic Peptides; Neprilysin; Pathway interactions; Patients; Persons; Population; Prevalence; Process; Production; Renin; Research Personnel; Risk; Serine Protease; Signal Pathway; Single Nucleotide Polymorphism; Staging; System; Testing; Tissues; Variant; Vasodilation; Work; atrial natriuretic factor receptor A; atrial natriuretic factor receptor B; autocrine; cohort; high risk; hypertensive heart disease; interest; mortality; paracrine; peptide hormone; pressure; programs; prospective; receptor; response

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.

描述（由申请人提供）：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，透析前人群中存在心血管疾病负担的增加。左心室肥厚 (LVH) 可能是慢性肾病 (CKD) 人群中研究最多的 CVD 标志物。在肾脏疾病的所有阶段，LVH 都预示着心血管发病率和死亡率的增加，并且 CKD 的每个阶段 LVH 的患病率都会增加。左心室质量（LV 质量）的增加（也称为同心重塑）可识别患有 CRI 的透析前患者罹患心血管疾病的高风险。利钠肽系统 (NPS) 可以对抗心脏肥大和纤维化的发展，并在 CRI 中被激活。 NPS 描述了心脏响应压力或容量超负荷合成和释放利钠肽（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-醛固酮系统的激活。此外，NPS 作为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 NPS 途径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) 中测试这些假设：这是一项由 NIH 资助的、多中心、前瞻性队列研究，针对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中同心心脏肥大增加和利钠肽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同心心脏肥大相关的假设，考虑上位相互作用最后，检验 corin 和相关 NPS 候选基因的遗传变异与 CRI 中收缩功能障碍和心力衰竭的发生相关的假设。