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：
10549718
负责人：
Girish Nitin Nadkarni
金额：
$ 70.03万
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/10549718
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 Disparity 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 Geography Goals Grant HIV Heavy Metals Hispanic Americans Individual Inflammatory Investigation Jackson Heart Study Kidney Kidney Diseases Link Machine Learning Maps 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 US State Underrepresented Minority Urine Urokinase Plasminogen Activator Receptor Variant biobank career development case control cell type clinical risk cohort deprivation design disorder risk ethnic disparity ethnic minority experience fine particles genetic association genetic risk factor genetic testing high risk improved inflammatory marker innovation insight large datasets meter minority communities minority patient multidisciplinary nephrotoxicity non-genetic novel podocyte racial determinant racial disparity 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.

项目摘要这是早期研究人员的应用，他的长期目标是研究决定者肾脏疾病的种族和种族差异。载脂蛋白L1（apol1）基因的风险变体 22号染色体在非洲血统（非裔美国人和非洲加勒比海西班牙裔的人）中很常见美国人），是迄今为止以频率和效果大小。这是肾脏疾病的重要发现，并进一步了解了肾脏疾病中的种族/种族分布。正在进行努力将APOL1基因检测纳入包括移植前评估和靶向疗法在内的临床环境即将到来。但是，存在两种风险变体（即Apol1高风险基因型，在多达14％的非裔美国人中看到 4％的非洲西班牙裔美国人）并未导致所有人明显的肾脏疾病。这不完整的渗透表明遗传或环境修饰符的主要作用，即“第二次命中”。尽管已经发现了一些遗传修饰剂，但由于缺乏以前的研究而受到阻碍样本量由于少数族裔的代表性不足而导致的样本量。空气之间也有很强的关联污染，不利的邻里环境（包括行走性和贫困）和足细胞有毒肾脏疾病和种族/少数民族的金属（砷，镉和汞）不成比例暴露于这些环境风险因素。我们提出了一种强大的研究策略，利用了几个大型数据集/人群全面研究apol1-的遗传和环境“第二次命中” 通过以下特定目的肾脏疾病关联：：识别和复制修改的SNP APOL1高风险基因型与肾脏疾病的关联（AIM 1）。使用遗传和临床数据〜70,000个少数族裔（〜5,400使用APOL1高风险基因型），我们将研究SNPS修改 APOL1高风险基因型与肾脏疾病之间的关联。然后，我们将执行顶部的复制在约25,000个独立个人中进行命中（使用APOL1高风险基因型的5,000个）。然后我们会评估空气污染的相互作用（颗粒物<2.5 µg或pm2.5）和不良测量使用APOL1高风险的邻居步行/贫困（AIM 2）使用地理上的潜水研究：生物群落生物库；杰克逊心脏学习和中风的地理和种族差异的原因（请注意）约40,000个个体（约3,600个APOL1高风险基因型）。最后，我们将探索砷，镉和汞的尿液水平与肾脏的APOL1高风险基因型之间的相互作用疾病在一项案例对照研究（n = 2,332）和探索性分析中的疾病中尿激酶型纤溶酶原激活剂接收器（SUPAR）水平 - 炎症性apol1修饰剂对此互动（目标3）。该提议将导致对遗传和环境“第二击”的关键见解 APOL1和对肾脏疾病中种族/种族差异的理解得到了提高。