A Genome Scan for Susceptibility to Helminthic Infection

描述（由申请人提供）：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，地蠕虫仍然是发展中国家发病率的主要原因，这表明迫切需要继续研究对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的2000个成员的数据，我们将蛔虫（蛔虫）、钩虫（美洲钩虫和十二指肠钩虫）和鞭虫（Trichuris trichiura）感染敏感性的主要数量性状位点定位到10个染色体区域。在研究的下一阶段，我们将测试对这些影响负责的特定基因的假设，作为首次研究的一部分，重点是鉴定对寄生虫感染的不同易感性负责的基因。该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STR标记对QTL区域进行精细定位，来完善影响蠕虫感染易感性的QTL定位。然后，我们将使用基因表达测定对位于狭窄连锁峰下的蠕虫感染差异易感性的候选基因进行优先排序。在决定对蠕虫感染的差异易感性的高优先候选基因中放置的snp的关联分析将用于确定哪些候选基因负责QTL效应。我们预计确定6个基因，我们将在50个人中重新排序以确定基因中的所有共同多态性，并使用数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键入功能变体，以确定哪些变体可以解释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.