Role of Genetic Susceptibility in the Central American Kidney Disease Epidemic

遗传易感性在中美洲肾脏病流行中的作用

• 批准号: 9986057
• 负责人: DANIEL R BROOKS
• 金额: $ 7.29万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9986057
• 关键词: Address; Affect; Agricultural Workers; Agriculture; Anti-inflammatory; Antibiotics; Area; Biology; Canes; Case-Control Studies; Central America; Central American; Chronic Kidney Failure; Clinical; Communicable Diseases; Communities; Costa Rica; Country; DNA; Data; Dependence; Diabetes Mellitus; Disease; Disease Clusterings; El Salvador; Enrollment; Environmental Exposure; Environmental Risk Factor; Epidemic; Exertion; Extended Family; Family; Frequencies; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Genotype; Goals; Government; Guatemala; Heat Stress Disorders; Heavy Metals; Hispanic Americans; Hispanics; Honduras; Hypertension; Individual; Industry; Infectious Agent; Kidney; Kidney Diseases; Longitudinal cohort; Maps; Mesoamerican; Mexico; Mining; Native Americans; Nephrology; Nicaragua; Occupations; Participant; Penetrance; Pesticides; Physicians; Population; Predisposition; Process; Public Health; Research; Research Design; Risk; Risk Factors; Role; Saccharum; Stress; Suggestion; Susceptibility Gene; Testing; United States; Urine; Validation; Variant; Water; Work; agricultural community; agricultural region; base; burden of illness; case control; causal variant; cohort; design; disorder risk; exome sequencing; family structure; genetic analysis; genetic approach; genetic epidemiology; genetic risk factor; genetic variant; genome wide association study; genome-wide; hot climate; kindred; member; nephrotoxicity; prospective; recruit; risk variant; statistics; sugar; validation studies; young man

PROJECT SUMMARY Extraordinarily high rates of chronic kidney disease have been observed on the Pacific coast of several Central American countries including Nicaragua, El Salvador, Honduras, Guatemala, Costa Rica, and Southern Mexico. This increasingly recognized epidemic of kidney disease, known as Mesoamerican Nephropathy (MeN), is not associated with traditional risk factors such as diabetes or hypertension, and affects predominately young men who work in agriculture. Environmental factors such as heat stress, pesticides, infectious diseases, and many others have been proposed as potential explanations, but no clear cause has emerged. The postulated risk factors do not appear to be unique to the affected region, and they do not explain why some agricultural workers get kidney disease while others do not. We propose that genetic susceptibility is a major contributor to MeN risk, a hypothesis that we have strengthened by documenting striking familial clustering of disease. We have built strong relationships with local physicians, workers' groups, industry, and government in a MeN hotspot in Nicaragua. We have also built an interdisciplinary team with expertise in nephrology, genetics, epidemiology, and statistics. We have successfully enrolled nearly 1400 participants in our studies and performed preliminary genetic analyses that strongly support a significant genetic susceptibility to MeN, including identification of one set of genetic variants associated with MeN at genome-wide significance levels. We propose to 1) conduct a case-control genome-wide association study of former sugar cane workers with MeN and current healthy workers, 2) study 40 large, multigenerational MeN kindreds using a family-based genetic approach, and 3) validate our findings and conduct additional SNP discovery in a longitudinal community-based cohort, as well as in miners and brick makers who are also affected by MeN. Our study design is optimized to identify genetic risk variants with different combinations of frequency, effect size, and dependence on environmental interactions. This project will illuminate genetic risk factors that cause susceptibility to kidney disease in people of mixed ancestry in our Central American neighbors and may also help us understand mechanisms that contribute to high rates of kidney disease in other populations with Native American or Hispanic ancestry.

项目概要 在太平洋沿岸观察到慢性肾病的发病率极高 一些中美洲国家，包括尼加拉瓜、萨尔瓦多、洪都拉斯、危地马拉、 哥斯达黎加和墨西哥南部。这种日益流行的肾脏疾病， 称为中美洲肾病 (MeN)，与传统危险因素无关 例如糖尿病或高血压，并且主要影响在工作中工作的年轻男性 农业。环境因素，如热应激、农药、传染病等 人们提出了许多其他的解释作为可能的解释，但还没有出现明确的原因。 假定的风险因素似乎并非受影响地区所独有，而且它们并不 解释为什么有些农业工人会患上肾病，而另一些则不会。我们建议 遗传易感性是 MeN 风险的一个主要因素，我们有这样的假设 通过记录疾病的显着家族聚集性来加强这一点。我们已经建立了强大的 MeN 中与当地医生、工人团体、行业和政府的关系 尼加拉瓜热点地区。我们还建立了一支具有肾脏病学专业知识的跨学科团队， 遗传学、流行病学和统计学。我们已成功报名近1400名参与者 在我们的研究中并进行了初步的遗传分析，有力地支持了重要的 对 MeN 的遗传易感性，包括鉴定一组相关的遗传变异 与 MeN 在全基因组显着性水平上。我们建议 1) 进行病例对照 对患有 MeN 的前甘蔗工人和当前健康人进行全基因组关联研究 工人，2) 使用基于家族的遗传学研究 40 个大型多代 MeN 亲属 方法，3) 验证我们的发现并在纵向中进行额外的 SNP 发现 以社区为基础的群体，以及也受到 MeN 影响的矿工和制砖商。 我们的研究设计经过优化，可识别具有不同组合的遗传风险变异 频率、效应大小以及对环境相互作用的依赖性。该项目将 阐明导致混合人群易患肾脏疾病的遗传风险因素 我们的中美洲邻国的祖先，也可能有助于我们理解机制 导致其他美洲原住民或其他人群的肾脏疾病发病率较高 西班牙裔血统。