Natural History of MYH9-Associated Nephropathy

描述(申请人提供)：严格的血压控制未能阻止非裔美国人高血压性肾病(HN)的发展，这表明除了高血压外，还有其他因素参与了疾病的病因。这项申请建议确定非裔美国人中与Myh9相关的HN的自然病史，因为Myh9占该民族所有非糖尿病终末期肾病(ESRD)病例的70%。所有Myh9风险等位基因纯合子的个体都不会发生肾脏疾病，这表明Myh9基因-环境和Myh9基因-基因相互作用促进了肾脏疾病的风险。这项申请建议招募和纵向评估那些由于与高血压相关的ESRD有一级亲属而有患HN高危的非裔美国人。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“二次打击”。将从参与者那里收集生物标本库，我们将测试HN的发展与暴露于潜在的易患肾脏疾病的病毒感染之间的联系。这种方法的基本原理是基于非裔美国人中Myh9风险单倍型与人类免疫缺陷病毒(HIV)相关性肾病(HIVAN)的强烈关联。HIVAN和HN均可表现为局灶节段性肾小球硬化。Myh9和其他HN易感基因之间的Myh9基因-基因交互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包括：(1)招募1,200名基于H-ESRD家族史的无血缘关系的HN高危非裔美国人，进行高血压、肾脏疾病和肾脏疾病风险因素的表型分析；(2)进行纵向跟踪，以确定Myh9基因多态性与横断面和纵向测量血压、蛋白尿、血清胱抑素C和肌酐浓度的关联，以及队列成员的估计肾小球滤过率；(3)创建生物标本库，以检测可能引发遗传易感者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，我们将能够确定具有和不具有Myh9肾病基因的亲属，并调查环境和遗传因素在肾脏疾病发展和进展中的作用。我们期望这项研究将有助于预测Myh9肾病家族进展为终末期肾病的风险。虽然对终末期肾病患者可能没有立竿见影的益处，但这项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生。这将使有风险的个人受益，他们可以从治疗干预中受益，以在早期阶段减轻疾病。对广大人群的预期好处超过了研究中涉及的最小风险。

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.