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

项目摘要

ABSTRACT OF PARENT PROJECT 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
园林工程简介 这是一位早期研究人员的申请,其长期目标是研究决定因素 肾脏疾病的种族和民族差异载脂蛋白L1(APOL 1)基因中的风险变体 22号染色体常见于非洲血统的人(非洲裔美国人和非洲-加勒比海西班牙裔 美国人),并且是迄今为止在频率方面确定的最强大的疾病变体之一, 效应大小这是肾脏疾病的一个重要发现,并进一步加深了我们对肾脏疾病的理解。 肾脏疾病的种族/民族差异。目前正在努力将APOL 1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即将出现。但 存在两个风险变量(即,APOL 1高风险基因型,见于高达14%的非洲裔美国人, 4%的非洲裔加勒比西班牙裔美国人)并不会导致所有个体出现明显的肾脏疾病。这 不完全遗传表明遗传或环境修饰剂的主要作用,“第二击”。 虽然已经发现了一些遗传修饰剂,但以前的研究因缺乏 由于少数民族代表性不足,样本量很大。空气与环境之间也有很强的联系, 污染,不利的邻里环境(包括步行能力和贫困)和足细胞毒性重 金属(砷,镉和汞)与肾脏疾病和种族/少数民族不成比例 暴露于这些环境风险因素。我们提出了一个强大的研究战略,利用几个大的 数据集/队列,以全面调查APOL 1的遗传和环境“二次打击”, 通过以下具体目的来研究肾脏疾病的关联: APOL 1高风险基因型与肾脏疾病的相关性(Aim 1)。使用遗传和临床数据, 约70,000名少数民族个体(约5,400名具有APOL 1高风险基因型),我们将研究修饰 APOL 1高风险基因型与肾脏疾病之间的关联然后,我们将执行复制顶部 在约25,000个独立个体中进行命中(约5,000个具有APOL 1高风险基因型)。然后我们将 评估空气污染(颗粒物<2.5 µg或PM2.5)与以下不利措施的相互作用: 社区步行能力/贫困与APOL 1肾脏疾病高风险(目标2),使用地理上不同的 研究:BioMe生物银行;杰克逊心脏研究和中风的地理和种族差异的原因 在约40,000名个体中(约3,600名具有APOL 1高风险基因型)。最后,我们将探讨 尿砷、镉、汞水平与APOL 1肾损害高危基因型的交互作用 在来自REGARDS的病例对照研究(n= 2,332)和探索性分析中, 尿激酶型纤溶酶原激活物受体(suPAR)水平--一种炎症性APOL 1修饰剂--影响这一点 相互作用(目标3)。这一建议将导致对遗传和环境的关键见解'二次打击', APOL 1和对肾脏疾病种族/民族差异的更好理解

项目成果

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Girish Nitin Nadkarni其他文献

Girish Nitin Nadkarni的其他文献

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{{ truncateString('Girish Nitin Nadkarni', 18)}}的其他基金

Artificial Intelligence to Predict Outcomes in Patients with Acute Kidney Injury on Continuous Renal Replacement Therapy
人工智能预测急性肾损伤患者连续肾脏替代治疗的结果
  • 批准号:
    10658576
  • 财政年份:
    2023
  • 资助金额:
    $ 66.21万
  • 项目类别:
Artificial Intelligence to Predict Outcomes in Patients with Acute Kidney Injury on Continuous Renal Replacement Therapy
人工智能预测急性肾损伤患者连续肾脏替代治疗的结果
  • 批准号:
    10261059
  • 财政年份:
    2020
  • 资助金额:
    $ 66.21万
  • 项目类别:
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:
    10318592
  • 财政年份:
    2020
  • 资助金额:
    $ 66.21万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 66.21万
  • 项目类别:
Risk Clustering and Stratification in Genetically High-Risk Individuals Using Electronic Medical Records and Biomarkers
使用电子病历和生物标记对遗传高危个体进行风险聚类和分层
  • 批准号:
    9180312
  • 财政年份:
    2016
  • 资助金额:
    $ 66.21万
  • 项目类别:

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  • 批准号:
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Molecular and Genetic Signatures of Perturbed Diabetic Pathways with Hepatitis C Virus infection and Co-morbidity Risks in African American Population
丙型肝炎病毒感染引起的糖尿病通路紊乱的分子和遗传特征以及非洲裔美国人的共病风险
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丙型肝炎病毒感染引起的糖尿病通路紊乱的分子和遗传特征以及非洲裔美国人的共病风险
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