Genetic Epidemiology of Chagas Disease Progression

描述(申请人提供)：恰加斯病影响着1700万人，另有1亿人面临感染克氏锥虫的风险，这是查加斯病的寄生原因，在整个拉丁美洲。每年约有30万人罹患恰加斯病，造成巨大的卫生保健负担。克鲁兹旋毛虫在美国的流行率正在上升，对血库样本(来自表面上健康的人)的调查显示，患病率从每5000人中有1人到9000人中有1人不等。大约40%的感染者在他们的一生中将保持无症状。然而，大约60%的感染者会进展为慢性恰加斯病。查加斯病的心脏形式使人非常虚弱，导致进行性心肌病。目前还没有针对克氏毛滴虫感染的疫苗，而且现有的药物在减少感染急性期后的寄生虫血症方面的效果也存在疑问。目前尚无治疗恰加斯病的有效药物。不幸的是，慢性恰加斯病的发病机制仍然知之甚少。我们将评估1000名感染克氏毛滴虫的人的心电图和与恰加斯病相关的免疫学表型，这些人属于大型扩展家系。该项目的目标是在该样本中确定进展为查加斯病心脏形式的基因决定因素。这些个体将具有100万个SNP的特征，以促进全基因组分析，旨在识别影响疾病进展的基因。来自这些相同家系的另外500名未感染的人将被用来帮助识别具体涉及到逐个感染的基因型相互作用的遗传变异。然后将对10个最有希望的基因进行重新测序，以确定导致所观察到的疾病进展表型差异的功能变异。最后，将在500名患有严重心脏病的无关感染病例和500名无症状的无关感染对照中进行最佳相关序列变异的确认性研究。对决定疾病进展的因果相关基因的了解将极大地促进我们对恰加斯病潜在发展机制的了解，建议在潜在的药物开发努力中考虑新的途径，并使现有的药物化合物与遗传分析所建议的新药物靶点相匹配。公共卫生意义：恰加斯病影响着1700万人，另有1亿人面临感染克氏锥虫的风险，这是恰加斯病的寄生原因，在整个拉丁美洲。每年约有30万人罹患恰加斯病，造成巨大的卫生保健负担。目前还没有针对克氏毛滴虫感染的疫苗，也没有针对慢性恰加斯病的有效疫苗。对决定疾病进展的因果相关基因的了解将极大地促进我们对恰加斯病潜在发展机制的了解，建议在潜在的药物开发努力中考虑新的途径，并使现有的药物化合物与遗传分析所建议的新药物靶点相匹配。

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.