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

• 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
• 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

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.

项目总结 这是一个有长期目标研究决定因素的早期研究人员的申请。 肾脏疾病方面的种族和民族差异。载脂蛋白L1(APOL1)基因的风险变异 22号染色体在非洲血统的人(非洲裔美国人和非裔加勒比拉美裔)中很常见 美国人)，是迄今为止发现的最强大的疾病变种之一，就频率和 效果大小。这是肾脏疾病的一项重要发现，加深了我们对 肾脏疾病方面的种族/民族差异。目前正在努力将APOL1基因检测纳入 包括移植前评估和靶向治疗在内的临床环境正在形成。然而， 存在两种风险变异(即APOL1高危基因类型，见于高达14%的非裔美国人和 4%的非裔加勒比裔拉美裔美国人)并不是所有人都会导致明显的肾脏疾病。这 不完全外显表明遗传或环境修饰物的主要作用，即“二次打击”。 尽管已经发现了一些遗传修饰物，但之前的研究因缺乏 由于少数群体代表性不足，样本数量较少。空气和空气之间也有很强的联系 污染，不良的邻里环境(包括可步行和贫困)和足细胞有毒重 患有肾脏疾病和种族/少数民族的金属(砷、镉和汞)不成比例 暴露在这些环境风险因素之下。我们提出了一个稳健的研究战略，利用几个大型 数据集/队列，全面调查APOL1的遗传和环境‘二次命中’- 通过以下特定目标与肾脏疾病关联：：识别和复制改变 APOL1高危基因与肾脏疾病的关系(目标1)。利用遗传和临床数据 大约70,000名少数民族个体(~5,400名具有APOL1高危基因的人)，我们将研究SNPs改变 载脂蛋白1高危基因与肾脏疾病的相关性。然后，我们将执行顶部的复制 在约25,000名独立个体(约5,000名具有APOL1高危基因型的个体)中进行命中。到时候我们会的 评估空气污染(颗粒物&lt；2.5微克或PM2.5)与 使用不同地理位置的APOL1肾病高危人群的社区可步行性/贫困(目标2) 研究：生物群生物库；杰克逊心脏研究和中风地理和种族差异的原因 (关于)约40,000人(约3,600人具有APOL1高危基因型别)。最后，我们将探讨 尿砷、镉、汞水平与肾脏载脂蛋白1高危基因的交互作用 病例对照研究中的疾病(n=2,332)和探索性分析中评估是否可解决 尿激酶型纤溶酶原激活物受体(SuPAR)水平--一种炎性APOL1修饰物--会影响这一点 互动(目标3)。这项提议将带来对基因和环境的批判性见解，为 APOL1和提高了对肾脏疾病的种族/民族差异的认识。