Genetic Epidemiology of Chagas Disease Progression

描述（由申请人提供）：南美锥虫病影响1700万人，另有1亿人有感染克氏锥虫的风险，克氏锥虫是南美锥虫病的寄生虫原因。每年大约有30万人患上恰加斯病，造成巨大的卫生保健负担。T.克鲁兹感染在美国不断增长，对血库样本（来自表面健康的个人）的调查显示，患病率在1/5000至1/9000之间。大约40%的感染者将在其一生中保持无症状。然而，大约60%的感染者会发展成慢性恰加斯病。心脏形式的恰加斯病是高度衰弱的，导致进行性心肌病。目前还没有针对T.克氏感染和现有药物在减少感染初期急性期后的寄生虫血症方面的效力值得怀疑。没有有效的药物治疗南美锥虫病。不幸的是，慢性恰加斯病的潜在发展机制仍然知之甚少。我们将在1000例感染锥虫病的个体中评估与锥虫病相关的ECG和免疫表型。cruzi和属于大的扩展谱系。该项目的目标是确定该样本中发展为心脏型恰加斯病的遗传决定因素。这些个体将被表征为100万个SNP，以促进旨在鉴定影响疾病进展的基因的全基因组分析。来自这些相同家系的另外500名未感染个体将用于帮助鉴定特异性参与基因型-感染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，以确定导致疾病进展中观察到的表型变异的功能变体。最后，将在500例无亲缘关系的严重心脏病感染病例和500例无亲缘关系的无症状感染对照中进行最佳关联序列变异的确认研究。了解与疾病进展有关的基因将大大提高我们对恰加斯病发展机制的认识，提出在潜在药物开发工作中要考虑的新途径，并允许将可用的药物化合物与遗传分析提出的新药靶点相匹配。公共卫生相关性：南美锥虫病影响到1 700万人，另有1亿人面临感染克氏锥虫的风险，克氏锥虫是南美锥虫病的寄生虫病因。每年大约有30万人患上恰加斯病，造成巨大的卫生保健负担。目前还没有针对T.克氏锥虫病对慢性锥虫病无效。了解与疾病进展有关的基因将大大提高我们对恰加斯病发展机制的认识，提出在潜在药物开发工作中要考虑的新途径，并允许将可用的药物化合物与遗传分析提出的新药靶点相匹配。

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.