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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：
8451330
负责人：
MARTIN R. POLLAK
金额：
$ 40.67万
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/8451330
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 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 risk variant screening transcription factor yeast two hybrid system

项目摘要

SUMMARY 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 were 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.

总结