Elucidating Genetic and Environmental Second Hits in Racial and Ethnic Minorities with APOL1 High-Risk Genotypes

阐明 APOL1 高风险基因型对少数种族和族裔的遗传和环境二次打击

基本信息

批准号：
10318592
负责人：
Girish Nitin Nadkarni
金额：
$ 61.75万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-14 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10318592
关键词：
Address Affect African American population African Caribbean African ancestry Air Pollution Apolipoproteins Arsenic Biological Assay Cadmium Case-Control Studies Chromosome 22 Chronic Kidney Failure Clinical Clinical Data Communities Data Disease Disease Outcome Early treatment End stage renal failure Ensure Environment Environmental Exposure Environmental Risk Factor Evaluation Exposure to Face Frequencies Genes Genetic Genetic Risk Genetic study Genotype Geographic state Geography Goals Grant HIV Heavy Metals Hispanic Americans Individual Inflammatory Investigation Jackson Heart Study Kidney Kidney Diseases Link Machine Learning Measures Mercury Metabolic Metal exposure Metals Methods Minority Groups Minority Health Research Modification Mutation Neighborhoods Other Genetics Outcome Particulate Matter Penetrance Persons Positioning Attribute Poverty Preventive Reasons for Geographic And Racial Differences in Stroke Reporting Research Research Personnel Resources Risk Risk Factors Role Sample Size Single Nucleotide Polymorphism Testing Therapeutic Time Transplantation Underrepresented Minority Urine Urokinase Plasminogen Activator Receptor Variant biobank career development case control cell type clinical risk cohort deprivation design disease disparity disorder risk ethnic minority experience fine particles genetic association genetic testing high risk improved inflammatory marker innovation insight large datasets minority communities minority patient multidisciplinary nephrotoxicity non-genetic novel podocyte racial and ethnic racial and ethnic disparities racial determinant racial minority risk stratification risk variant socioeconomics targeted treatment urinary walkability

项目摘要

PROJECT SUMMARY This is an application by an early stage investigator who has the long-term objective of studying determinants of racial and ethnic disparities in kidney disease. Risk variants in the Apolipoprotein L1 (APOL1) gene on chromosome 22 are common in persons of African ancestry (African Americans and Afro-Caribbean Hispanic Americans) and are one of the most powerful disease variants identified to date in terms of frequency and effect size. This is an important discovery for kidney disease and has furthered our understanding of racial/ethnic disparities in kidney disease. There are efforts underway to incorporate APOL1 genetic testing in clinical settings including in pre-transplant evaluation and targeted therapies are on the horizon. However, the presence of two risk variants (i.e. the APOL1 high-risk genotypes, seen in up to 14% of African Americans and 4% of Afro-Caribbean Hispanic Americans) does not lead to overt kidney disease in all individuals. This incomplete penetrance indicates a major role of either genetic or environmental modifiers i.e. ‘second hits’. Although some genetic modifiers have been discovered, previous studies have been hampered by lack of sample sizes due to underrepresentation of minorities. There are also strong associations between air pollution, adverse neighborhood environment (including walkability and poverty) and podocyte toxic heavy metals (Arsenic, Cadmium and Mercury) with kidney disease and racial/ethnic minorities are disproportionately exposed to these environmental risk factors. We propose a robust research strategy leveraging several large datasets/cohorts to comprehensively investigate the genetic and environmental ‘second-hits’ for the APOL1- kidney disease association through the following Specific Aims: : To identify and replicate SNPs that modify the association of the APOL1 high-risk genotypes with kidney disease (Aim 1). Using genetic and clinical data on ~70,000 minority individuals (~5,400 with APOL1 high-risk genotypes), we will investigate SNPs modifying the association between APOL1 high-risk genotype and kidney disease. We will then perform replication of the top performing hits in ~25,000 independent individuals (~5,000 with APOL1 high-risk genotypes). We will then assess the interaction of air pollution (particulate matter<2.5 µg or PM2.5) and adverse measures of neighborhood walkability/poverty with APOL1 high-risk for kidney disease (Aim 2) using geographically diverse studies: BioMe Biobank; Jackson Heart Study and REasons for Geographic and Racial Differences in Stroke (REGARDS) in ~40,000 individuals (~3,600 with APOL1 high-risk genotypes). Finally, we will explore the interaction between urine levels of Arsenic, Cadmium and Mercury with APOL1 high-risk genotypes for kidney disease in a case-control study from REGARDS (n=2,332) and in exploratory analyses assess whether soluble urokinase-type plasminogen activator receptor (suPAR) levels-an inflammatory APOL1 modifier-affects this interaction (Aim 3). This proposal will lead to critical insights on genetic and environmental ‘second hits’ for APOL1 and improved understanding of racial/ethnic disparities in kidney disease.

项目概要这是早期研究人员的申请，其长期目标是研究决定因素载脂蛋白 L1 (APOL1) 基因中的种族和民族差异。 22 号染色体常见于非洲血统的人（非裔美国人和非裔加勒比西班牙裔）美国人），是迄今为止在频率和频率方面发现的最强大的疾病变异之一这是肾脏疾病的一个重要发现，加深了我们对肾脏疾病的认识。肾脏疾病中的种族/民族差异正在努力将 APOL1 基因检测纳入其中。然而，包括移植前评估和靶向治疗在内的临床环境即将到来。存在两种风险变异（即 APOL1 高风险基因型，在高达 14% 的非裔美国人中出现） 4% 的非裔加勒比裔美国人）不会导致所有个体出现明显的肾脏疾病。不完全外显率表明遗传或环境修饰剂的主要作用，即“第二次打击”。尽管已经发现了一些基因修饰剂，但之前的研究因缺乏证据而受到阻碍。由于少数群体代表性不足，样本量也存在很大的关联性。污染、不良的邻里环境（包括步行性和贫困）和足细胞毒性重金属（砷、镉和汞）与肾病和少数种族/族裔的关系不成比例面对这些环境风险因素，我们提出了一项强有力的研究策略，利用几个大的因素。数据集/队列全面调查 APOL1 的遗传和环境“二次打击” 肾脏疾病协会通过以下具体目标：识别和复制改变肾脏疾病的 SNP APOL1 高风险基因型与肾脏疾病的关联（目标 1）。约 70,000 名少数族裔个体（约 5,400 名具有 APOL1 高风险基因型），我们将调查修改然后我们将进行顶部复制。然后我们将在约 25,000 名独立个体（约 5,000 名具有 APOL1 高风险基因型）中进行命中。评估空气污染（颗粒物 <2.5 µg 或 PM2.5）和不利措施的相互作用使用不同地理位置的 APOL1 肾病高风险（目标 2）的社区步行能力/贫困研究：BioMe 生物银行；杰克逊心脏研究以及中风的地理和种族差异的原因（问候）约 40,000 人（约 3,600 人具有 APOL1 高风险基因型）最后，我们将探讨。尿液中砷、镉和汞含量与 APOL1 肾脏高危基因型之间的相互作用 REGARDS 的病例对照研究 (n=2,332) 和探索性分析评估疾病是否可溶尿激酶型纤溶酶原激活剂受体 (suPAR) 水平（一种炎症 APOL1 修饰剂）会影响这一点该提案将带来关于遗传和环境“第二次打击”的重要见解。 APOL1 并提高了对肾脏疾病中种族/民族差异的了解。