Role of Genetic Susceptibility in the Central American Kidney Disease Epidemic

项目总结 在太平洋沿岸观察到了极高的慢性肾脏疾病发病率 几个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。越来越多人认识到肾脏疾病的流行， 被称为中美洲肾病(男性)，与传统的危险因素无关 如糖尿病或高血压，主要影响在 农业。环境因素，如热应激、杀虫剂、传染病和 其他许多人也提出了可能的解释，但没有明确的原因出现。 假定的风险因素似乎并不是受影响地区独有的，它们也不是 解释为什么一些农业工人会得肾病，而另一些人则不会。我们建议 遗传易感性是男性风险的主要贡献者，这是我们已经有的假设 通过记录疾病的显著家族性聚集性而得到加强。我们已经建立了强大的 男性与当地医生、工人团体、行业和政府的关系 尼加拉瓜的热点地区。我们还建立了一支拥有肾脏病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，有力地支持了 对男性的遗传易感性，包括确定一组相关的遗传变异 与男性在全基因组意义上的水平。我们建议1)进行病例对照 前甘蔗工人与男性和现在健康人群的全基因组关联研究 工人，2)使用基于家庭的基因研究40个大的、多代人的男性亲属 方法，以及3)验证我们的发现并在纵向上进行额外的SNP发现 在以社区为基础的队列中，以及在矿工和制砖工人中，也受到男性的影响。 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、影响大小和对环境相互作用的依赖。这个项目将 阐明导致混合血液病患者肾脏疾病易感性的遗传危险因素 我们中美洲邻国的祖先，也可能有助于我们理解 导致其他美洲原住民或其他人群肾病发病率高的原因 西班牙裔血统。

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.