Genetic Epidemiology of Chagas Disease Progression

恰加斯病进展的遗传流行病学

基本信息

批准号：
8101324
负责人：
SARAH A. WILLIAMS-BLANGERO
金额：
$ 77.68万
依托单位：
TEXAS BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8101324
关键词：
Acute Address Affect Area Biological Assay Blood Banks Brazil Cardiac Cardiomyopathies Cardiovascular Pathology Central America Chagas Disease Characteristics Chronic DNA DNA Resequencing Data Data Collection Data Set Development Disease Outcome Disease Progression Drug Delivery Systems Electrocardiogram Family Future Genes Genetic Genetic Determinism Genome Genotype Goals Grant Health Healthcare Heart Diseases Incidence Individual Infection Knowledge Latin America Lead Longitudinal Studies Measures Molecular Motivation Organism Parasitemia Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Population Study Predisposition Prevalence Process Public Health Reading Research Research Design Risk Sampling Scanning Serum Severity of illness South America Surveys Systems Analysis Technology Testing Trypanosoma cruzi United States Universities Vaccines Variant Work base care burden cohort density design drug development effective therapy experience follow-up forest genetic analysis genetic epidemiology genetic pedigree genetic variant genome wide association study genome-wide improved novel response rural area transmission process

项目摘要

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.

描述（由申请人提供）：查加斯疾病影响1700万人，另外1亿人面临着锥虫锥虫的危险，这是整个拉丁美洲的chagas疾病的寄生虫原因。每年大约有30万人出现chagas疾病，导致巨大的医疗保健负担。在美国，克鲁兹感染的患病率正在增长，血库样本的调查（来自显然健康的个体）显示出患病率在5000和9000中的1分中1至1分之间。大约40％的感染者将在一生中保持无症状。但是，大约60％的感染者将发展为慢性查加斯病。 Chagas病的心脏形式高度令人衰弱，导致进行性心肌病。没有针对克鲁氏霉菌感染的疫苗，可用的药物在最初的急性感染后减少寄生虫血症具有可疑功效。没有有效的chagas疾病药物治疗方法。不幸的是，慢性查加斯疾病的发展的机制仍然很少了解。我们将评估1000名感染T. cruzi并属于大型延长的谱系的人中与Chagas疾病相关的ECG和免疫表型。该项目的目的是确定该样本中chagas病的心脏形式的遗传决定因素。这些人将以100万个SNP的特征来促进旨在识别影响疾病进展的基因的全基因组分析。来自这些相同血统的另外500名未感染的个体将被用来帮助鉴定遗传变异，这些遗传变异特异性涉及逐型基因型的相互作用。然后，将重新计算出10个最有前途的基因，以识别负责观察到的疾病进展表型变异的功能变异。最后，将在500例患有严重心脏疾病的无关感染病例和500个无关感染无症状对照的无关感染病例中对最佳相关序列变体进行确认研究。了解与疾病进展的因果关系的知识将显着提高我们对chagas疾病开发机制的知识，提出在潜在药物开发工作中考虑的新途径，并允许将可用的药物化合物与新的药物靶向相匹配。通过遗传分析。公共卫生相关性：夏加斯病影响1700万人，另外1亿人面临着整个拉丁美洲锥虫病的锥虫锥虫菌（Cruzi）感染的风险。每年大约有30万人出现chagas疾病，导致巨大的医疗保健负担。没有针对克鲁氏菌感染的疫苗，也没有有效的慢性查加斯病。了解与疾病进展的因果关系的知识将显着提高我们对chagas疾病开发机制的知识，提出在潜在药物开发工作中考虑的新途径，并允许将可用的药物化合物与新的药物靶向相匹配。通过遗传分析。