A Genome Scan for Susceptibility to Helminthic Infection

描述(申请人提供)：土壤传播的蠕虫感染是主要的国际卫生问题，影响到世界四分之一以上的人口。尽管有有效的药物可用，但地球蠕虫仍然是发展中国家发病的主要原因，这表明迫切需要继续研究这类重要感染的易感性决定因素。该项目在过去五年中开展的工作表明，对蠕虫感染的易感性有重要的遗传因素。利用一个尼泊尔家系2000名成员的数据，我们将蛔虫(蛔虫)、钩虫(美洲钩虫和十二指肠钩虫)和鞭虫(鞭虫)感染易感性的主要数量性状基因座定位到总共10个染色体区域。在拟议的下一阶段研究中，我们将测试有关导致这些影响的特定基因的假设，这是有史以来第一项专注于识别对寄生虫感染的不同易感性的基因的研究的一部分。这项研究的总体目标是确定负责QTL效应的特定基因，并表征这些基因中的功能变异。我们将通过使用额外的STR标记对QTL区域进行精细定位来精炼影响蠕虫感染易感性的QTL的定位。然后，我们将使用基因表达分析来优先考虑位于缩小的连锁峰下的蠕虫感染的不同易感性的位置候选基因。对被放置在决定蠕虫感染差异易感性基因的高优先级候选基因中的SNP进行关联分析，以确定哪些候选基因对QTL效应负责。我们预计将确定6个基因，我们将在50人中对这些基因进行重新测序，以确定这些基因中所有常见的多态，并使用定量性状核苷酸分析来确定功能变异。随后，我们将在更大的数据集中输入功能变体，以确定哪些变体解释了QTL效应。

DESCRIPTION (provided by applicant): The soil-transmitted helminthic infections are major international health concerns, affecting over a quarter of the world's population. Despite the availability of effective drugs, geohelminths persist as major causes of morbidity in the developing world, indicating the critical need for continued research on the determinants of susceptibility to this important class of infections. Work conducted by this project during the last five years has demonstrated that there are significant genetic components to susceptibility to helminthic infections. Using data generated for 2000 members of a single Nepalese pedigree, we have localized major quantitative trait loci effects on susceptibility to roundworm (Ascaris lumbricoides), hookworm (Necatur americanus and Ancylostoma duodenale), and whipworm (Trichuris trichiura) infection to a total of 10 chromosomal regions. In the proposed next phase of the study, we will test hypotheses about the specific genes responsible for these effects as part of the first study ever focused on the identification of genes responsible for differential susceptibility to a parasitic infection. The overall goal of the research is to identify the specific genes responsible for the QTL effects and characterize the functional variants within those genes. We will refine the localization of QTLs influencing susceptibility to helminthic infection by fine mapping of QTL regions with additional STR markers. We will then use gene expression assays to prioritize positional candidate genes for differential susceptibility to helminthic infection located under the narrowed linkage peak. Association analyses of SNPs placed within high priority candidates for genes determining differential susceptibility to helminthic infection will be used to determine which candidates are responsible for the QTL effects. We anticipate identifying 6 genes, which we will resequence in 50 people to identify all common polymorphisms in the genes and use quantitative trait nucleotide analysis to identify the functional variants. Subsequently we will type the functional variants in larger data sets to determine which variants account for the QTL effect.