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50万美国人患有末期肾脏疾病（ESRD）。非裔美国人以比欧洲人高4-5倍的肾衰竭发展。最近，我们发现了载脂蛋白1（APOL1）中的两个编码序列变体，这些变体占了这一主要健康差异的很大比例。 APOL1肾脏疾病变体对多种不同类型的肾脏疾病有重大影响，包括高血压相关的ESRD，局灶性节段性肾小球硬化症（FSGS）和与HIV相关的肾病（Hivan）。风险遗传是隐性的：具有两个变异APOL1等位基因的个体具有7-30倍的肾脏疾病风险。我们预测，超过350万非裔美国人具有高风险的APOL1基因型。在所有个体中，存在两个风险等位基因的存在并没有导致肾脏疾病，这表明其他遗传和环境因素是重要的修饰符。理解为什么有些具有高风险基因型的人会发展肾脏疾病，而另一些人则不会改善风险分层，并可能阐明最适合治疗的途径。因此，我们建议：目标1：在APOL1基因座上确定其他遗传修饰剂。我们的数据表明，Apol1肾脏疾病风险变异是功能等位基因。由于不是所有有两个风险的人等位基因发生疾病，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编码突变的作用。我们将定义可能改变apol1基因表达的结构变体，并测试它们对两种疾病等位基因的渗透率的影响。我们将测试转录因子和microRNA结合位点中的多态性是否会影响这些APOL1风险等位基因的外观。 AIM 2：找到APOL1渗透率的上皮修饰符。至少部分是因为它们提供了防止锥虫的保护，APOL1肾脏风险变体的频率在非洲的频率上增加。我们假设同时选择了其他遗传基因座，以防止肾脏损伤。编码风险等位基因，这些基因座的保护作用可能会减少与欧洲人混合后。在这里，我们将对全基因组进行多态性，以防止或加剧APOL1变体诱导的肾损伤。我们将确定与野生类型和编码变体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剂。在其他风险因素的情况下，Apol1肾脏疾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基因型相互作用以引起肾脏疾病。维生素D被认为可以防止肾脏损伤，而某些脂质特征可能会促进损伤。我们询问这些分子是否会在体外改变APOL1生物学，以及这些介体的生化水平是否预测哪些患有APOL1风险基因型的人可能会发展肾脏疾病。