Natural History of MYH9-Associated Nephropathy

MYH9 相关肾病的自然史

• 批准号: 7698171
• 负责人: BARRY Ira FREEDMAN
• 金额: $ 62.16万
• 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/7698171
• 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; Homozygote; Hypertension; Immunofluorescence Immunologic; Individual; Infection; Injury; Kidney; Kidney Diseases; Laboratories; Life Style; Light; 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; member; minimal risk; non-diabetic; novel; podocyte; post gamma-globulins; proband; public health relevance; 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中高血压肾脏硬化（HN）的进展，这表明除了高血压外，还涉及疾病因果关系。该申请建议在非洲裔美国人中确定与MYH9相关的HN的自然史，因为MYH9占该族裔终末期肾脏疾病（ESRD）的所有非糖尿病病例的70％。所有纯合为MYH9风险等位基因的人都不会患上肾脏疾病，这表明MYH9基因环境和MYH9基因相互作用会导致肾脏疾病风险。该申请提议招募和纵向评估非裔美国人，这些非洲裔美国人由于拥有与高血压相关的ESRD的一级亲戚而受到高风险的HN风险。导致肾脏疾病的生活方式和环境因素的影响将被评估为与MYH9相关肾病的潜在“第二次命中”。将从参与者那里收集生物标本的存储库，我们将测试HN的发展与暴露于潜在的病毒感染可能会诱发肾脏疾病的关联。这种方法的基本原理是基于MYH9风险单倍型与非洲裔美国人与人类免疫缺陷病毒（HIV）相关的肾病（HIVAN）的密切关联。 Hivan和HN可能都作为局灶性节段性肾小球硬化。 MYH9基因与其他HN敏感性基因之间的MYH9基因相互作用的作用将与我们正在进行的R01 DK070941共同探索。该项目的主要组成部分是：（1）根据H-ESRD的家族史，招募了1,200名HN风险高的非裔美国人受试者，并具有出现高血压，肾脏疾病和肾脏疾病风险因素的表型； （2）纵向随访，以确定MYH9基因多态性与血压的横截面和纵向测量，蛋白尿，血清胱抑素C和肌酐浓度以及估计的队列成员肾小球滤过速率的关联； （3）创建生物标本的存储库来检测可能引发遗传易感个体中与MYH9相关的肾病的环境因素。我们将测试与HN相关的潜在病毒感染的证据（MYH9基因 - 环境相互作用）。公共卫生相关性：从这项研究中，我们将能够确定有或没有MYH9肾病基因型的亲戚，并研究环境和遗传因素对肾脏疾病发展和进展的作用。我们预计这项研究将有助于预测MYH9-氯性病家庭中ESRD发展的风险。尽管ESRD患者可能没有立即的好处，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育。这将使有可能受益于治疗干预措施的人受益于早期阶段的疾病。预期的对人口的收益大于研究所涉及的最小风险。