Natural History of MYH9-Associated Nephropathy

描述（由申请人提供）：严格的血压控制并不能阻止非裔美国人高血压性肾硬化（HN）的进展，提示除高血压外的其他因素也参与了疾病的病因。该应用旨在确定非裔美国人MYH9相关HN的自然史，因为MYH9占该种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-基因相互作用有助于肾脏疾病的风险。本研究拟招募并纵向评估因一级亲属患有高血压相关ESRD而具有HN高风险的非裔美国人。生活方式和环境因素对肾病的影响将被评估为myh9相关肾病的潜在“第二打击”。将从参与者那里收集生物标本，我们将测试HN的发展与暴露于潜在的易患肾脏疾病的潜伏病毒感染之间的关系。这种方法的基本原理是基于非裔美国人MYH9风险单倍型与人类免疫缺陷病毒（HIV）相关肾病（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基因与其他HN易感基因之间的相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是：(1)招募1200名非裔美国人，根据H-ESRD家族史，无亲缘关系，存在高血压、肾脏疾病和肾脏疾病危险因素；(2)纵向随访，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和肌酐浓度以及估计的肾小球滤过率之间的关系；(3)建立生物标本库，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：从这项研究中，我们将能够识别患有和不患有MYH9肾病基因型的亲属，并研究环境和遗传因素在肾脏疾病发生和进展中的作用。我们期望这项研究将有助于预测myh9肾病家庭发展为ESRD的风险。虽然对ESRD患者可能没有直接的益处，但该研究将有助于预测需要密切监测哪些MYH9风险纯合子以预防肾病的发展。这将使有风险的个体受益，他们可以从治疗干预中获益，在早期阶段减轻疾病。总的来说，预期对人群的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.