Natural History of MYH9-Associated Nephropathy

MYH9 相关肾病的自然史

• 批准号: 8142969
• 负责人: BARRY Ira FREEDMAN
• 金额: $ 52.99万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142969
• 关键词: AIDS-Associated Nephropathy; Accounting; Affect; African American; Albuminuria; Alleles; Angiotensin-Converting Enzyme Inhibitors; Biochemical; Biopsy; Blood Pressure; Chronic Kidney Failure; Clinical; Clinical Research; Communicable Diseases; Creatinine; Cytoskeleton; DNA; Detection; Development; Disease; Electron Microscopy; End stage renal failure; Environment; Environmental Risk Factor; Epidemiologist; Ethnic group; Etiology; Exposure to; Family; Family history of; First Degree Relative; Focal Segmental Glomerulosclerosis; Future; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genotype; Glomerular Filtration Rate; HIV; Haplotypes; Health; Homozygote; Hypertension; Immunofluorescence Microscopy; Individual; Infection; Injury; Kidney; Kidney Diseases; Laboratories; Measures; Monitor; Natural History; Nephrosclerosis; Obesity; Participant; Patients; Peptide Initiation Factors; Phenotype; Plasma; Population; Public Health; Questionnaires; Recruitment Activity; Relative (related person); Risk; Risk Factors; Role; Sampling; Secondary Hypertension; Serum; Smoking; Specialist; Specimen; Staging; Staining method; Stains; Susceptibility Gene; Testing; Therapeutic Intervention; Tissues; Urine; Variant; Virus Diseases; Work; base; blood pressure regulation; cohort; disorder risk; follow-up; gene environment interaction; gene interaction; genetic epidemiology; high risk; lifestyle factors; light microscopy; member; minimal risk; non-diabetic; novel; podocyte; post gamma-globulins; proband; repository; treatment strategy

DESCRIPTION (provided by applicant): Strict blood pressure control fails to halt the progression of hypertensive nephrosclerosis (HN) in African Americans, suggesting that factors in addition to high blood pressure are involved in disease causation. This application proposes to determine the natural history of MYH9-associated HN in African Americans, as MYH9 accounts for 70% of all non- diabetic cases of end-stage renal disease (ESRD) in this ethnic group. All individuals who are homozygous for MYH9 risk alleles do not develop kidney disease, demonstrating that MYH9 gene-environment and MYH9 gene-gene interactions contribute to kidney disease risk. This application proposes to recruit and longitudinally evaluate African American individuals who are at high risk for developing HN by virtue of having a first degree relative with hypertension-associated ESRD. The impact of lifestyle and environmental factors causing kidney disease will be evaluated as potential "second hits" for MYH9-associated nephropathy. A repository of biologic specimens will be collected from participants and we will test for association between development of HN and exposure to latent viral infections potentially predisposing to kidney disease. The rationale for this approach is based on the strong association of MYH9 risk haplotypes with Human Immunodeficiency Virus (HIV)-associated nephropathy (HIVAN) in African Americans. HIVAN and HN may both present as focal segmental glomerulosclerosis. The role of MYH9 gene-gene interaction between MYH9 and other HN susceptibility genes would be explored in concert with our ongoing R01 DK070941. The major components of this project are: (1) recruitment of 1,200 unrelated African American subjects at high risk for HN based upon family history of H-ESRD, with phenotyping for the presence of hypertension, kidney disease and kidney disease-risk factors; (2) longitudinal follow-up to determine the association of MYH9 gene polymorphisms with cross-sectional and longitudinal measures of blood pressure, albuminuria, serum cystatin C and creatinine concentrations, and estimated glomerular filtration rates in members of the cohort; and (3) creation of a repository of biologic specimens to detect environmental factors that may trigger MYH9-associated nephropathy in genetically susceptible individuals. We will test for evidence of latent viral infections associated with HN (MYH9 gene-environment interactions). PUBLIC HEALTH RELEVANCE: From this study we will be able to identify relatives with and without the MYH9 nephropathy genotype and investigate the role of environmental and genetic factors on the development and progression of kidney disease. We expect that this study will aid in predicting risk for progressing to ESRD in families with MYH9-nephropathy. While there may be no immediate benefit to ESRD patients, the study will help anticipate which MYH9 risk homozygotes need to be closely monitored for development of nephropathy. This will benefit individuals at risk who could benefit from therapeutic intervention to alleviate disease at an earlier stage. The anticipated benefits to the population at large outweigh the minimal risk involved in the study.

描述（由申请人提供）：严格的血压控制无法阻止非裔美国人高血压肾硬化（HN）的进展，这表明除高血压之外的其他因素也与该疾病有关。本申请旨在确定非裔美国人中 MYH9 相关 HN 的自然史，因为 MYH9 占该种族群体中所有非糖尿病终末期肾病 (ESRD) 病例的 70%。所有 MYH9 风险等位基因纯合的个体都不会患肾病，这表明 MYH9 基因-环境和 MYH9 基因-基因相互作用会增加肾病风险。本申请拟招募并纵向评估因一级亲属患有高血压相关 ESRD 而处于发生 HN 高风险的非裔美国人。导致肾脏疾病的生活方式和环境因素的影响将被评估为 MYH9 相关肾病的潜在“第二次打击”。将从参与者那里收集生物样本库，我们将测试 HN 的发展与暴露于可能诱发肾脏疾病的潜在病毒感染之间的关联。这种方法的基本原理是基于 MYH9 风险单倍型与非裔美国人中人类免疫缺陷病毒 (HIV) 相关肾病 (HIVAN) 的密切相关性。 HIVAN 和 HN 均可能表现为局灶节段性肾小球硬化。 MYH9 与其他 HN 易感基因之间的 MYH9 基因-基因相互作用的作用将与我们正在进行的 R01 DK070941 一起探索。该项目的主要组成部分是：（1）根据 H-ESRD 家族史招募 1,200 名具有 HN 高风险的无关非裔美国受试者，并对是否存在高血压、肾脏疾病和肾脏疾病危险因素进行表型分析； (2) 纵向随访，以确定 MYH9 基因多态性与队列成员的横断面和纵向血压、蛋白尿、血清胱抑素 C 和肌酐浓度以及估计肾小球滤过率的相关性； (3) 创建生物样本库，以检测可能在遗传易感个体中引发 MYH9 相关肾病的环境因素。我们将测试与 HN（MYH9 基因-环境相互作用）相关的潜伏病毒感染的证据。公共卫生相关性：通过这项研究，我们将能够识别有或没有 MYH9 肾病基因型的亲属，并研究环境和遗传因素对肾病发生和进展的作用。我们期望这项研究将有助于预测 MYH9 肾病家族进展为 ESRD 的风险。虽然 ESRD 患者可能不会立即受益，但该研究将有助于预测哪些 MYH9 风险纯合子需要密切监测肾病的发展。这将使处于危险中的个体受益，他们可以从治疗干预中受益，以在早期阶段缓解疾病。对广大人群的预期收益超过了研究中涉及的最小风险。