Genetic Risk Factors for Visceral Leishmaniasis

描述（由申请人提供）：致命寄生虫病内脏利什曼病（cVL）的三个主要全球疫点发生在印度、苏丹和巴西。80-90%的人类感染为亚临床或无症状，通常与强细胞介导免疫相关，可导致皮肤试验延迟型超敏试验（DTH+）对利什曼抗原呈阳性。这个项目的目标是了解为什么同样暴露于利什曼病的个体会经历不同的感染结果。之前对cVL的遗传研究不足以有信心地检查候选基因，或找到影响cVL或DTH反应复杂表型的所有基因。我们现在已经积累了足够的样本量，可以自信地进行假设驱动的候选基因等位基因关联研究，并进行基于snp芯片的全基因组关联扫描（GWAS）。事实上，基于snp芯片的印度cVL全基因组关联扫描（GWAS）和巴西cVL/DTH应答的初步研究将在2008/9年度完成。本RO1的目标是：1。为了验证候选基因（SLC11A1, IL4-LECT2/TGFBI， HLA）使用密集标签snp决定cVL和无症状感染（DTH+）易感性的假设，样本量足以研究这些复杂的疾病表型。2. 通过对印度1000例cVL病例和1000例对照进行的基于人群的原发性GWAS的阳性结果验证，确定新的易感基因和相关的功能性病因变异，使用基于密集标签snp家族的等位基因关联试验（控制1217个扩展cVL家族的种族），重新测序，生物信息学分析以及mRNA和蛋白质表达分析。3. 通过对巴西家族中cVL（626）、DTH+(1160)或DTH-(900)表型个体进行的基于家族的初级GWAS结果进行验证，利用基于密集标签snp家族的等位基因关联、重测序、生物信息学分析以及mRNA和蛋白质表达分析，鉴定新的易感性和耐药基因以及相关的功能性病因变异。遗传学研究的一个主要目的是确定导致疾病发病的基因/机制/途径。通过上述研究验证的基因通路分析将用于确定在cVL发病机制中重要的免疫、生化和分子途径。这项研究有可能证明相同的分子途径在不同地理区域/利什曼原虫物种中是重要的，也有可能发现提供群体特异性疾病易感性的特定遗传多态性。这项研究可以为新的功能研究提供种子，这些研究可以转化为未来的疾病干预措施。公共卫生相关性：致命寄生虫病内脏利什曼病仅发生在接触利什曼原虫的一小部分人群中。这个项目的目标是使用遗传方法来确定为什么相同暴露的个体会经历不同的感染结果。这项研究将确定决定疾病易感性的基因和途径，这可能转化为未来的疾病干预措施。

DESCRIPTION (provided by applicant): Three major worldwide foci of the fatal parasitic disease visceral leishmaniasis (cVL) occur in India, Sudan and Brazil. 80-90% of human infections are sub-clinical or asymptomatic, usually associated with strong cell-mediated immunity which can result in a positive skin-test delayed type hypersensitivity test (DTH+) to leishmanial antigen. The goal of this project is to understand why individuals with the same exposure to leishmaniasis experience different outcomes of infection. Prior genetic studies of cVL have been underpowered to examine candidate genes with confidence, or to find all genes influencing the complex phenotypes of cVL or DTH response. We have now accumulated sample sizes of sufficient power to carry out hypothesis-driven candidate gene allelic association studies with confidence, and to perform SNP-chip based genome-wide association scans (GWAS). Indeed, primary SNP-chip based genome-wide association scans (GWAS) of cVL from India and cVL/DTH response in Brazil will be completed during 2008/9. Aims of this RO1 are: 1. To test the hypothesis that candidate genes (SLC11A1, IL4-LECT2/TGFBI, HLA) determine susceptibility to cVL and to asymptomatic infection (DTH+) using dense tag-SNPs, with sample sizes that are sufficiently powered to study these complex disease phenotypes. 2. To identify novel susceptibility genes and associated functional etiological variants by validating the positive results of the population-based primary GWAS being performed on 1000 cVL cases and 1000 controls from India, using dense tag-SNP family-based allelic association tests that control for ethnicity in 1217 extended cVL families, re-sequencing, bioinformatic analysis, and mRNA and protein expression analysis. 3. To identify novel susceptibility and resistance genes and associated functional etiological variants, by validating results of the family-based primary GWAS being performed on individuals with cVL (626), DTH+ (1160) or DTH- (900) phenotypes in Brazilian families, using dense tag-SNP family-based allelic association, re-sequencing, bioinformatic analysis, and mRNA and protein expression analysis. A major aim of genetic studies is to identify genes/mechanisms/pathways that contribute to the pathogenesis of disease. Pathway analysis of genes validated by the above studies will be used to define immunological, biochemical and molecular pathways that are important in the pathogenesis of cVL. This study has the potential to demonstrate that the same molecular pathways are important across different geographic regions/Leishmania species, and also to discover specific genetic polymorphisms that provide population-specific susceptibility to disease. The study could seed novel functional studies that could translate into future disease intervention measures. PUBLIC HEALTH RELEVANCE: The fatal parasitic disease visceral leishmaniasis occurs in only a subset of people exposed to the Leishmania parasite. The goal of this project is use a genetic approach to determine why individuals with the same exposure experience different outcomes of infection. The study will define genes and pathways that determine disease susceptibility, which could translate into future disease intervention measures.