Genetic Determinants of Hypertensive Heart Disease in CRI

CRI 中高血压心脏病的遗传决定因素

基本信息

批准号：
7845804
负责人：
Daniel L Dries
金额：
$ 25.73万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845804
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

项目摘要

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）是铬肾功能不全（CRI）患者发病率和死亡率的主要原因。 CVD仍然是透析患者和接受肾脏移植的患者死亡的主要原因。有证据表明，在透析前的人群中，CVD负担的增加。左心室肥大（LVH）可能是慢性肾脏疾病（CKD）种群中CVD的最佳研究标记。在肾脏疾病的所有阶段，LVH都可以预测心血管发病率和死亡率的增加以及CKD每个阶段LVH的普遍性增加。左心肿块（LV质量）的增加，也称为同心重塑，可以识别出心血管疾病高风险的CRI前患者。亚替尼肽系统（NP）反对心脏肥大和纤维化的发展，并在CRI中被激活。 NPS描述了心脏合成和释放亚替肽的能力（心理纳替肽[ANP]，脑Natriuretic肽[BNP]和C型Natriuretic肽[CNP]），以应对压力或体积过载。 ANP，BNP和CNP发挥了全身作用，包括血管舒张，纳地尿和肾素 - 血管烯醛酮系统的激活减少。此外，NPS充当了直接相反心脏肥大和纤维化的自分泌和旁分泌系统。该项目的中心假设是，在慢性肾脏不足（CRI）的情况下，科林和相关NPS途径基因的遗传变异有助于高血压心脏病的发展。感兴趣的候选基因是：Corin，Furin，ANP，BNP，CNP，NPR-A，NPR-B，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：NIH赞助的，多中心的前瞻性队列研究对受试者的心血管疾病（n = 3000），患有慢性肾脏不足。我们将检验以下假设：CORIN基因的遗传变异与CRI中的同心心脏肥大和脂肪耐药性损害有关，测试假说，假设与Corin相关的NPS候选基因的遗传变异与同心心脏肥大有关在这些候选基因之间，最后检验了Corin和相关NPS候选基因遗传变异的假设与CRI中收缩功能障碍和入射心力衰竭的发展有关。