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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：
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
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/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

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.

项目总结