Genetic Epidemiology of Chagas Disease Progression

描述（由申请人提供）：在整个拉丁美洲，恰加斯病影响1700万人，另有1亿人面临感染克氏锥虫的风险，克氏锥虫是恰加斯病的寄生虫病因。每年约有30万人患恰加斯病，造成巨大的卫生保健负担。在美国，克氏锥虫感染的流行率正在上升，对血库样本（来自表面上健康的个体）的调查显示，患病率在5000分之一到9000分之一之间。大约40%的感染者终生无症状。然而，约60%的感染者将发展为慢性恰加斯病。恰加斯病的心脏形式是高度衰弱，导致进行性心肌病。目前还没有针对克氏锥虫感染的疫苗，现有药物在感染初期急性期后减少寄生虫血症的功效值得怀疑。目前还没有有效的药物治疗恰加斯病。不幸的是，慢性恰加斯病发展的潜在机制仍然知之甚少。我们将评估与恰加斯病相关的心电图和免疫表型，涉及1000名感染克氏锥虫且属于大型扩展谱系的个体。该项目的目标是确定该样本中恰加斯病进展为心脏形式的遗传决定因素。这些个体将被表征为一百万个snp，以促进旨在确定影响疾病进展的基因的全基因组分析。另外500名来自相同家谱的未感染个体将被用于帮助鉴定与基因型-感染相互作用有关的遗传变异。然后将对10个最有希望的基因进行重新测序，以确定导致疾病进展中观察到的表型变异的功能变异。最后，将在500例不相关的严重心脏病感染病例和500例不相关的无症状感染对照中进行最佳相关序列变异的确认研究。对决定疾病进展的基因的了解将大大提高我们对恰加斯病发展机制的认识，为潜在药物开发工作提供新的途径，并允许将现有药物化合物与遗传分析建议的新药物靶点进行匹配。公共卫生相关性：整个拉丁美洲，恰加斯病影响到1 700万人，另有1亿人面临感染恰加斯病寄生虫克氏锥虫的风险。每年约有30万人患恰加斯病，造成巨大的卫生保健负担。目前还没有针对克氏锥虫感染的疫苗，也没有针对慢性恰加斯病的有效疫苗。对决定疾病进展的基因的了解将大大提高我们对恰加斯病发展机制的认识，为潜在药物开发工作提供新的途径，并允许将现有药物化合物与遗传分析建议的新药物靶点进行匹配。

DESCRIPTION (provided by applicant): Chagas disease affects 17 million people and a further 100 million people are at risk for infection with Trypanosoma cruzi, the parasitic cause of Chagas disease, throughout Latin America. Approximately 300,000 people develop Chagas disease each year resulting in an enormous health care burden. The prevalence of T. cruzi infection is growing in the U.S., and surveys of blood bank samples (from apparently healthy individuals) show prevalence rates ranging between 1 in 5000 and 1 in 9000. Approximately 40% of infected individuals will remain asymptomatic throughout their lives. However, about 60% of infected individuals will progress to chronic Chagas disease. The cardiac form of Chagas disease is highly debilitating, resulting in progressive cardiomyopathy. There is no vaccine for T. cruzi infection and available drugs are of questionable efficacy in reducing parasitemia after the initial acute phase of infection. There are no effective pharmaceutical treatments for Chagas disease. Unfortunately, the mechanisms underlying development of chronic Chagas disease remain poorly understood. We will assess ECG and immunological phenotypes correlated with Chagas disease in 1000 individuals who are infected with T. cruzi and who belong to large extended pedigrees. The goal of the project is to identify genetic determinants of progression to the cardiac form of Chagas disease in this sample. These individuals will be characterized for one million SNPs to facilitate genome-wide analyses designed to identify genes influencing disease progression. An additional 500 uninfected individuals from these same pedigrees will be employed to aid the identification of genetic variants that specifically are involved in genotype-by-infection interaction. The 10 most promising genes will then be resequenced to identify the functional variants responsible for the observed phenotypic variation in disease progression. Finally, a confirmation study of the best associated sequence variants will be performed in 500 unrelated infected cases with severe cardiac disease and 500 unrelated infected asymptomatic controls. Knowledge of the genes that are causally involved in determination of disease progression will significantly advance our knowledge of mechanisms underlying development of Chagas disease, suggest new pathways to be considered in potential drug development efforts, and allow matching of available pharmaceutical compounds to novel drug targets suggested by genetic analysis. PUBLIC HEALTH RELEVANCE: Chagas disease affects 17 million people and a further 100 million people are at risk for infection with Trypanosoma cruzi, the parasitic cause of Chagas disease, throughout Latin America. Approximately 300,000 people develop Chagas disease each year resulting in an enormous health care burden. There is no vaccine for T. cruzi infection and no effective for chronic Chagas disease. Knowledge of the genes that are causally involved in determination of disease progression will significantly advance our knowledge of mechanisms underlying development of Chagas disease, suggest new pathways to be considered in potential drug development efforts, and allow matching of available pharmaceutical compounds to novel drug targets suggested by genetic analysis.