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

• 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
• 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

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(申请人提供)：超过500,000名美国人患有终末期肾病。非洲裔美国人患肾衰竭的几率是欧洲裔美国人的4-5倍。最近，我们发现了载脂蛋白L1(APOL1)的两个编码序列变体，它们在这种重大的健康差异中占了很大比例。APOL1肾病变异体对多种不同类型的肾脏疾病有重大影响，包括高血压相关性终末期肾病、局灶节段性肾小球硬化(FSGS)和艾滋病毒相关性肾病(HIVAN)。风险遗传是隐性的：携带两个变异的APOL1等位基因的个体患肾脏疾病的风险增加7-30倍。我们预测，超过350万非裔美国人拥有高危APOL1基因。两个风险等位基因的存在并不会导致所有个体的肾脏疾病，这表明其他遗传和环境因素是重要的修饰因素。了解为什么一些具有高危基因的人会患上肾脏疾病，而另一些人不会，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：确定APOL1基因座上的其他遗传修饰物。我们的数据表明，APOL1肾病风险变异是功能获得性等位基因。因为并不是所有有两种风险的人 等位基因导致疾病，其他局部多态可能调节APOL1的表达，调节导致疾病的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性的影响。我们将测试转录因子和microRNA结合位点的多态是否会影响这些APOL1风险等位基因的外显性。目的2：寻找载脂蛋白1外显性的上位性修饰语。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对锥虫的保护。我们假设，同时选择了额外的遗传基因座来保护肾脏免受主要 编码风险等位基因，这些基因座的保护作用在与欧洲人混合后可能已经减弱。在这里，我们将进行全基因组筛查，寻找可能预防或加剧APOL1变异引起的肾损伤的基因多态。我们将鉴定与野生型和编码变异体APOL1有差异结合的蛋白质，因为这些结合伙伴可能调节风险变异体造成的损伤。目的3：寻找APOL1介导的肾脏疾病的生化修饰因子。在设定其他危险因素时，APOL1肾病风险变异体可能是最有害的。在这里，我们探索两个重要的因素如何与APOL1基因相互作用而导致肾脏疾病。维生素D被认为对肾脏损伤具有保护作用，而某些脂类可能会促进损伤。我们问这些分子是否会在体外改变APOL1的生物学，以及这些介体的生化水平是否可以预测哪些APOL1风险基因携带者有可能患上肾脏疾病。