Genetic Risk Factors for Visceral Leishmaniasis

内脏利什曼病的遗传风险因素

• 批准号: 8115035
• 负责人: Jenefer Mary Blackwell
• 金额: $ 31.61万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8115035
• 关键词: Abbreviations; Anemia; Antigens; Biochemical; Bioinformatics; Biology; Body Weight decreased; Brazil; Candidate Disease Gene; Cellular Immunity; Child health care; Clinical; Collaborations; Competitive Bidding; Complex; Computer Simulation; Country; Delayed Hypersensitivity; Development; Disease; Disease Outcome; Disease susceptibility; Endemic Diseases; Environmental Risk Factor; Ethnic Origin; Exposure to; Family; Fever; Functional RNA; Future; Gene Frequency; Genes; Genetic; Genetic Polymorphism; Geographic Locations; Goals; Haplotypes; Health; Human; Hypersensitivity skin testing; IL4 gene; Immune response; India; Individual; Infection; Institutes; Interferons; Interleukin-4; Intervention; Iron; Knowledge; Leishmania; Leishmaniasis; Linkage Disequilibrium; Liver; Maps; Measures; Minor; Molecular; Montenegro; Names; Odds Ratio; Outcome; Parasites; Parasitic Diseases; Pathogenesis; Pathway Analysis; Pathway interactions; Phenotype; Polymerase Chain Reaction; Population; Predisposition; Public Health; Quantitative Trait Loci; Recording of previous events; Research; Resistance; Reverse Transcription; Risk Factors; Role; Sample Size; Sampling; Seeds; Single Nucleotide Polymorphism; Spleen; Sudan; Susceptibility Gene; Susceptibility/Resistance Gene; T cell response; TGFBI gene; Testing; Time; Translating; Trust; Variant; Visceral Leishmaniasis; base; career development; case control; clinical phenotype; cytokine; disease phenotype; experience; genetic risk factor; genome wide association study; genome-wide analysis; genome-wide linkage; improved; lymph nodes; lymphocyte proliferation; mRNA Expression; macrophage; novel; population based; protein expression; response; trafficking; transmission process

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.

描述（由申请方提供）：致死性寄生虫病内脏利什曼病（cVL）的三个主要全球疫源地发生在印度、苏丹和巴西。80-90%的人类感染是亚临床或无症状的，通常与强细胞介导的免疫力相关，其可导致对利什曼原虫抗原的皮肤试验迟发型超敏反应试验（DTH+）阳性。该项目的目标是了解为什么暴露于利什曼病的个体会经历不同的感染结果。先前的cVL遗传学研究已经不足，以检查候选基因的信心，或找到所有的基因影响cVL或DTH反应的复杂表型。我们现在已经积累了足够的样本量进行假设驱动的候选基因等位基因关联研究的信心，并进行基于SNP芯片的全基因组关联扫描（GWAS）。事实上，印度cVL和巴西cVL/DTH反应的主要基于SNP芯片的全基因组关联扫描（GWAS）将在2008/9年完成。本RO 1的目标是：1。为了检验候选基因（SLC 11 A1、IL 4-LECT 2/TGFBI、HLA）决定对cVL和无症状感染（DTH+）的易感性的假设，使用密集标签SNP，样本量足以研究这些复杂的疾病表型。2.通过验证对来自印度的1000例cVL病例和1000例对照进行的基于人群的主要GWAS的阳性结果，识别新型易感基因和相关功能性病因学变体，使用基于密集tag-SNP家族的等位基因关联测试，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.通过对巴西家族中具有cVL（626）、DTH+（1160）或DTH-（900）表型的个体进行基于家族的主要GWAS的结果进行验证，使用基于密集tag-SNP家族的等位基因关联、重新测序、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学变体。遗传学研究的一个主要目的是确定有助于疾病发病机制的基因/机制/途径。通过上述研究验证的基因的通路分析将用于定义在cVL发病机制中重要的免疫学、生物化学和分子通路。这项研究有可能证明相同的分子途径在不同的地理区域/利什曼原虫物种中是重要的，并且还发现了提供人群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：致命的寄生虫病内脏利什曼病只发生在一个子集的人暴露于利什曼原虫。该项目的目标是使用遗传方法来确定为什么具有相同暴露的个体会经历不同的感染结果。该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。