Role of Genetic Susceptibility in the Central American Kidney Disease Epidemic

项目摘要 在太平洋沿岸， 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。这种日益被认可的肾病流行病， 被称为中美洲肾病（MeN），与传统的风险因素无关 如糖尿病或高血压，主要影响在农村工作的年轻男子， 农业环境因素，如热应激、杀虫剂、传染病和 还有许多其他可能的解释，但没有明确的原因。 假设的风险因素似乎并不是受影响地区所独有的，而且它们也不是 解释为什么有些农业工人会得肾病，而另一些则不会。我们提出 遗传易感性是导致MeN风险的一个主要因素，这是一个假设， 通过记录惊人的家族性疾病聚集性而得到加强。我们确立了强劲 与当地医生，工人团体，工业和政府在一个医疗网络的关系， 尼加拉瓜的热点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经成功招募了近1400名参与者 在我们的研究中，并进行了初步的遗传分析，强烈支持一个重要的 对MeN的遗传易感性，包括鉴定一组相关的遗传变异 与MeN在全基因组显著性水平。我们建议1）进行病例对照 前甘蔗工人与MeN和目前健康的全基因组关联研究 工人，2）研究40个大的，多代MeN kinetics使用基于家庭的遗传 方法，和3）验证我们的发现，并进行额外的SNP发现在纵向 社区人群以及矿工和制砖工人也受到MeN的影响。 我们的研究设计进行了优化，以确定具有不同组合的遗传风险变体， 频率、效应大小和对环境相互作用的依赖。该项目将 阐明导致混合人群对肾脏疾病易感性的遗传风险因素 我们中美洲邻国的祖先，也可能帮助我们了解机制， 导致其他美洲原住民或 西班牙血统

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.