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）：严格的血压控制未能阻止非洲裔美国人高血压肾硬化（HN）的进展，这表明除高血压外的因素也参与了疾病的病因。本申请提出确定非裔美国人中MYH 9相关HN的自然史，因为MYH 9占该种族群体中终末期肾病（ESRD）的所有非糖尿病病例的70%。所有MYH 9风险等位基因纯合的个体不会发生肾脏疾病，这表明MYH 9基因-环境和MYH 9基因-基因相互作用有助于肾脏疾病风险。本申请拟招募和纵向评价因一级亲属患有高血压相关ESRD而具有发生HN高风险的非裔美国人。生活方式和环境因素对肾脏疾病的影响将被评估为MYH 9相关肾病的潜在“二次打击”。将从受试者中收集生物标本库，我们将检测HN的发生与暴露于可能诱发肾脏疾病的潜伏性病毒感染之间的相关性。这种方法的基本原理是基于MYH 9风险单倍型与非裔美国人的人类免疫缺陷病毒（HIV）相关肾病（HIVAN）的强相关性。HIVAN和HN均可表现为局灶节段性肾小球硬化。MYH 9与其他HN易感基因之间的MYH 9基因-基因相互作用的作用将与我们正在进行的R 01 DK 070941一起探索。该项目的主要组成部分是：（1）招募1，200名无血缘关系的非裔美国人受试者，这些受试者具有高血压、肾脏疾病和肾脏疾病危险因素的表型，且具有H-ESRD家族史;（2）纵向随访，以确定MYH 9基因多态性与血压、蛋白尿、血清半胱氨酸蛋白酶抑制剂C和肌酐浓度，以及估计的肾小球滤过率在成员的队列;和（3）创建一个储存库的生物标本，以检测环境因素，可能会触发MYH 9相关的肾病遗传易感个体。我们将检测与HN（MYH 9基因-环境相互作用）相关的潜伏病毒感染的证据。公共卫生关系：从这项研究中，我们将能够确定有和没有MYH 9肾病基因型的亲属，并研究环境和遗传因素对肾脏疾病发展和进展的作用。我们希望这项研究将有助于预测MYH 9肾病家族进展为ESRD的风险。虽然对ESRD患者可能没有立即的益处，但该研究将有助于预测哪些MYH 9风险纯合子需要密切监测肾病的发展。这将使处于风险中的个人受益，他们可以从治疗干预中受益，以在早期阶段减轻疾病。对广大人群的预期受益超过了研究涉及的最小风险。