Genetic Risk Factors for Visceral Leishmaniasis

内脏利什曼病的遗传风险因素

• 批准号: 7577927
• 负责人: Jenefer Mary Blackwell
• 金额: $ 32.25万
• 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/7577927
• 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; Human; Hypersensitivity skin testing; Immune response; India; Individual; Infection; Institutes; Interferons; Interleukin-4; Intervention; Iron; Knowledge; Leishmania; Leishmaniasis; Linkage Disequilibrium; Liver; Maps; Measures; Messenger RNA; 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-Lymphocyte; 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; macrophage; novel; population based; protein expression; public health relevance; 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（由申请人提供）：全球致命寄生虫病内脏利什曼病（cVL）的三个主要疫源地发生在印度、苏丹和巴西。 80-90% 的人类感染是亚临床或无症状的，通常与强大的细胞介导的免疫有关，这可能导致对利什曼原虫抗原的皮试延迟型超敏反应试验 (DTH+) 呈阳性。该项目的目标是了解为什么同样接触利什曼病的个体会经历不同的感染结果。先前的 cVL 遗传学研究不足以自信地检查候选基因，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，可以充满信心地开展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 和巴西 cVL/DTH 反应的全基因组关联扫描 (GWAS) 将于 2008/9 年度完成。 RO1 的目的是： 1. 检验候选基因（SLC11A1、IL4-LECT2/TGFBI、HLA）使用密集标签 SNP 确定 cVL 和无症状感染 (DTH+) 易感性的假设，样本量足够有力研究这些复杂的疾病表型。 2. 通过验证对来自印度的 1000 个 cVL 病例和 1000 个对照进行的基于人群的主要 GWAS 的阳性结果，使用基于密集标签 SNP 家族的等位基因关联测试来识别新的易感基因和相关的功能性病因变异。对 1217 个扩展 cVL 家族进行种族分析、重测序、生物信息学分析以及 mRNA 和蛋白质表达分析。 3. 通过验证对巴西家庭中具有 cVL (626)、DTH+ (1160) 或 DTH- (900) 表型的个体进行的基于家庭的主要 GWAS 结果，鉴定新的易感性和抗性基因以及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、重测序、生物信息学分析以及 mRNA 和蛋白质表达分析。遗传学研究的一个主要目的是确定导致疾病发病机制的基因/机制/途径。上述研究验证的基因通路分析将用于定义在 cVL 发病机制中重要的免疫学、生化和分子通路。这项研究有可能证明相同的分子途径在不同地理区域/利什曼原虫物种中很重要，并且还可以发现提供特定人群对疾病易感性的特定遗传多态性。这项研究可能会催生新的功能研究，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仅发生在接触利什曼原虫寄生虫的一小部分人中。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。该研究将定义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。