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

基本信息

批准号：
9978780
负责人：
DANIEL R BROOKS
金额：
$ 70.22万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
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/9978780
关键词：
Address Affect Agricultural Workers Agriculture Anti-Inflammatory Agents 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 genomic locus hot climate kindred member nephrotoxicity prospective recruit risk variant statistics sugar validation studies young man

项目摘要

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.

项目摘要在太平洋海岸已经观察到了慢性肾脏疾病的高率包括尼加拉瓜，萨尔瓦多，洪都拉斯，危地马拉的几个中美洲国家哥斯达黎加和墨西哥南部。这种越来越公认的肾脏疾病流行，被称为中美洲肾病（男性）与传统危险因素无关例如糖尿病或高血压，并主要影响从事工作的年轻人农业。环境因素，例如热应激，农药，传染病和许多其他人被认为是潜在的解释，但没有出现明确的理由。假定的危险因素似乎并不是受影响区域的独特之处，它们也不是解释为什么有些农业工作者患上肾脏疾病而另一些人则没有。我们建议这种遗传易感性是导致男性风险的主要因素，这是我们有一个假设通过记录引人注目的疾病家族聚类来加强。我们已经建立了强大与当地医师，工人团体，行业和政府的关系尼加拉瓜的热点。我们还建立了一个具有肾脏学专业知识的跨学科团队，遗传学，流行病学和统计学。我们已经成功招募了近1400名参与者在我们的研究并进行了初步遗传分析中，强烈支持重要的对男性的遗传敏感性，包括鉴定一组相关的遗传变异男性处于全基因组显着性水平。我们建议1）进行病例对照全基因组协会研究以前的甘蔗工人与男性和当前健康工人，2）研究40个大型多代男性使用基于家庭的遗传 3）验证我们的发现并在纵向中进行其他SNP发现基于社区的队列以及也受男性影响的矿工和砖制造商。我们的研究设计经过优化，以确定具有不同组合的遗传风险变异频率，效果大小以及对环境相互作用的依赖。这个项目将阐明遗传危险因素，导致混合患者对肾脏疾病的敏感性我们中美洲邻国的祖先，也可以帮助我们了解机制在其他美洲原住民或西班牙裔血统。