APOL1 variants: Understanding the basis of disparities in rates of kidney disease

APOL1 变异：了解肾脏疾病发病率差异的基础

基本信息

批准号：
8282062
负责人：
MARTIN R. POLLAK
金额：
$ 43.5万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8282062
关键词：
AIDS-Associated Nephropathy Accounting Address Admixture Affect Africa African African American African Trypanosomiasis Alleles American Binding Binding Sites Biochemical Biological Assay Biology Caring Code Data Disease Employee Strikes End stage renal failure Environmental Risk Factor Epidemic European Focal Segmental Glomerulosclerosis Frequencies Gene Expression Gene Frequency Genes Genetic Genetic Polymorphism Genotype Hereditary Disease Human Human Genetics Hypertension In Vitro Individual Injury Kidney Kidney Diseases Kidney Failure Lead Lipids Mediating Mediator of activation protein MicroRNAs Mutation Other Genetics Pathway interactions Penetrance Protein Binding Public Health Renal function Renal glomerular disease Resistance Risk Risk Factors Screening procedure Stratification Testing Trypanosoma United States Variant Vitamin D Yeasts base disorder risk gain of function genetic variant genome wide association study health disparity high risk improved protective effect transcription factor yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): More than 500,000 Americans suffer from end-stage renal disease (ESRD). African Americans develop kidney failure at rates 4-5 fold higher than European Americans. Recently, we discovered two coding sequence variants in ApolipoproteinL1 (APOL1) that account for a large proportion of this major health disparity. APOL1 kidney disease variants have a major impact on multiple different types of kidney disease including hypertension-associated ESRD, focal segmental glomerulosclerosis (FSGS), and HIV-associated nephropathy (HIVAN). Risk inheritance is recessive: individuals with two variant APOL1 alleles have a 7-30 fold increased risk for kidney disease. We predict that more than 3.5 million African Americans have the high-risk APOL1 genotype. The presence of two risk alleles does not lead to kidney disease in all individuals, indicating that other genetic and environmental factors are important modifiers. Understanding why some individuals with the high-risk genotype develop kidney disease while others do not will improve risk stratification and may illuminate the pathways most amenable to therapy. We therefore propose to: Aim 1: Identify additional genetic modifiers at the APOL1 gene locus. Our data suggest that APOL1 kidney disease risk variants are gain-of- function alleles. Since not all individuals with two risk alleles develop disease, other local polymorphisms may regulate expression of APOL1, modulating the effect of the disease-causing APOL1 coding mutations. We will define structural variants that may alter APOL1 gene expression, and test their effects on the penetrance of the two disease-causing alleles. We will test whether polymorphisms in transcription factor and microRNA binding sites affect the penetrance of these APOL1 risk alleles. Aim 2: Find epistatic modifiers of APOL1 penetrance. The APOL1 renal risk variants increased in frequency in Africa, at least in part, because they provided protection against trypanosomes. We hypothesize that additional genetic loci is simultaneously selected that protect against renal injury from the major coding risk alleles, and that the protective effect of these loci may have diminished after admixture with Europeans. Here, we will perform a genome-wide screen for polymorphisms that may protect against or exacerbate APOL1 variant-induced renal injury. We will identify proteins that bind differentially to wild type and coding variant ApoL1, as these binding partners may modulate injury caused by the risk variants. Aim 3: Identify biochemical modifiers of APOL1-mediated renal disease. ApoL1 kidney disease risk variants may be most deleterious in the setting of additional risk factors. Here, we explore how two important factors may interact with APOL1 genotype to cause renal disease. Vitamin D is believed to be protective against renal injury, while certain lipid profiles may promote injury. We ask whether these molecules alter APOL1 biology in vitro, and whether biochemical levels of these mediators predict which individuals with the APOL1 risk genotype are likely to develop kidney disease.

描述（由申请人提供）：超过 500,000 名美国人患有终末期肾病 (ESRD)。非裔美国人患肾衰竭的比率是欧洲裔美国人的 4-5 倍。最近，我们在载脂蛋白 L1 (APOL1) 中发现了两个编码序列变异，它们在这一重大健康差异中占了很大比例。 APOL1 肾脏疾病变异对多种不同类型的肾脏疾病具有重大影响，包括高血压相关的 ESRD、局灶节段性肾小球硬化症 (FSGS) 和 HIV 相关肾病 (HIVAN)。风险遗传是隐性的：具有两个 APOL1 等位基因变异的个体患肾脏疾病的风险增加 7-30 倍。我们预测超过 350 万非裔美国人具有高风险 APOL1 基因型。两个风险等位基因的存在不会导致所有个体出现肾脏疾病，这表明其他遗传和环境因素是重要的调节因素。了解为什么一些具有高风险基因型的个体会患上肾脏疾病，而其他人则不会，这将改善风险分层，并可能阐明最适合治疗的途径。因此，我们建议：目标 1：在 APOL1 基因位点识别其他遗传修饰剂。我们的数据表明 APOL1 肾病风险变异是功能获得等位基因。因为并非所有个人都有两种风险当等位基因发生疾病时，其他局部多态性可能调节 APOL1 的表达，从而调节引起疾病的 APOL1 编码突变的影响。我们将定义可能改变 APOL1 基因表达的结构变异，并测试它们对两个致病等位基因外显率的影响。我们将测试转录因子和 microRNA 结合位点的多态性是否影响这些 APOL1 风险等位基因的外显率。目标 2：找到 APOL1 外显率的上位修饰因子。 APOL1 肾脏风险变异在非洲的频率增加，至少部分是因为它们提供了针对锥虫的保护。我们假设同时选择了额外的基因位点，以防止主要的肾损伤编码风险等位基因，并且这些基因座的保护作用在与欧洲人混合后可能会减弱。在这里，我们将进行全基因组多态性筛选，这些多态性可能会预防或加剧 APOL1 变异引起的肾损伤。我们将鉴定与野生型和编码变体 ApoL1 差异结合的蛋白质，因为这些结合伴侣可能会调节风险变体引起的损伤。目标 3：确定 APOL1 介导的肾脏疾病的生化修饰因子。在存在其他危险因素的情况下，ApoL1 肾病风险变异可能是最有害的。在这里，我们探讨了两个重要因素如何与 APOL1 基因型相互作用而导致肾脏疾病。维生素 D 被认为可以预防肾损伤，而某些脂质成分可能会促进肾损伤。我们询问这些分子是否会在体外改变 APOL1 生物学，以及这些介质的生化水平是否可以预测哪些具有 APOL1 风险基因型的个体可能患上肾脏疾病。