Genetic Risk Factors for Visceral Leishmaniasis

内脏利什曼病的遗传风险因素

• 批准号: 8497571
• 负责人: Jenefer Mary Blackwell
• 金额: $ 29.71万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497571
• 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; 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.

描述（由申请人提供）：致命的寄生疾病内脏利什曼病（CVL）的三个主要全球焦点出现在印度，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有关，这可能会导致对利什曼抗原的正面测试延迟延迟类型的超敏反应测试（DTH+）。该项目的目的是了解为什么同样接触利什曼病的人会经历不同的感染结果。先前对CVL的遗传研究的能力不足以置信度检查候选基因，或者找到影响CVL或DTH反应的复杂表型的所有基因。现在，我们积累了足够的能力样本量，以信心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-CHIP的基于SNP芯片的基因组关联扫描（GWAS）。实际上，印度CVL的基于SNP芯片的主要基因组关联扫描（GWAS）和巴西的CVL/DTH反应将在2008/9期间完成。该RO1的目的是：1。用于检验候选基因（SLC11A1，IL4-莱克特2/TGFBI，HLA）的假设，以确定使用密度TAG-SNP的CVL和无症状感染（DTH+）的敏感性，具有足够动力的样本尺寸研究这些复杂的疾病表型。 2。通过使用密集的基于TAG-SNP家庭的等位基因关联测试对1000个CVL病例和1000个对照进行的基于人群的主要GWA的积极结果来识别新型敏感性基因和相关的功能性病因变异。 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。通过验证对CVL（626），DTH+（1160）或DTH-（900）表型的基于家庭的主要GWA的结果，确定新型的敏感性和抗性基因和相关的功能病因变异。使用密集的TAG-SNP家庭等位基因关联，重新测序，生物信息学分析以及mRNA和蛋白质表达分析。遗传研究的主要目的是鉴定有助于疾病发病机理的基因/机制/途径。通过上述研究验证的基因的途径分析将用于定义在CVL发病机理中很重要的免疫，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的地理区域/利什曼原虫物种中都很重要，并且还发现特定的遗传多态性，这些遗传多态性可提供特定于人群的疾病易感性。这项研究可以播种新的功能研究，可以转化为未来的疾病干预措施。