Fine-mapping Association Analysis of Total IgE on Chr. 20p12 in Costa Ricans

描述(由申请人提供)： 虽然哮喘在美国和拉丁美洲的拉美裔中是一个重要的公共卫生问题，但人们对遗传因素在这一民族哮喘发病机制中的作用知之甚少。我们之前已经在哥斯达黎加的一个基因隔离的拉美裔人群中发现了与染色体20p12上的总血清IgE相关的重要证据。这项建议试图确定染色体20p12上的血清总IgE-哮喘的关键中间表型-的遗传决定因素。我们将首先对哥斯达黎加哮喘男孩及其父母20p12号染色体上的血清总IgE进行精细定位关联分析。然后，我们将尝试在儿童哮喘管理计划(CAMP)中的白人(非西班牙裔)男孩家庭中复制积极的发现。在确定了男性总IgE的易感基因(S)后，我们将对哥斯达黎加和坎普的哮喘女孩家庭中新发现的候选基因进行关联研究，以评估我们研究结果的普适性。最后，我们将评估这些候选基因在CD4T淋巴细胞上的表达，并检查所选的变异是否会影响cAMP中哮喘儿童血清总IgE的基因表达特征。这项提议提供了一个独特的机会来确定哮喘易感基因(S)，特别是在拉美裔美国人中。关于公共卫生相关性的声明尽管在美国和拉丁美洲的某些拉美裔亚群中哮喘的负担不成比例，但人们对拉美裔哮喘的遗传学知之甚少。这项建议将利用最先进的遗传和基因组方法，帮助了解总体上，特别是在拉美裔美国人中，总血清IgE的遗传调节的一个组成部分，总血清IgE是哮喘的关键中间体。 (摘要结束)

DESCRIPTION (provided by applicant): Although asthma is a significant public health problem among Hispanics in the United States and in Latin America, little is known about the contribution of genetic factors to the pathogenesis of asthma in this ethnic group. We have previously identified significant evidence of linkage to total serum IgE on chromosome 20p12 among males in a genetically isolated Hispanic population in Costa Rica. This proposal seeks to identify genetic determinants of total serum IgE - a critical intermediate phenotype of asthma- on chromosome 20p12. We will first conduct a fine-mapping association analysis of total serum IgE on chromosome 20p12 in Costa Rican boys with asthma and their parents. We will then attempt to replicate positive findings among families of white (non-Hispanic) boys in the Childhood Asthma Management Program (CAMP). After identification of a susceptibility gene(s) for total IgE in males, we will assess the generalizability of our findings by performing association studies of newly identified candidate genes among families of girls with asthma in both Costa Rica and CAMP. Finally, we will assess the expression of these candidate genes on CD4+ T lymphocytes and examine whether selected variants affect gene expression signatures for total serum IgE among children with asthma in CAMP. This proposal offers a unique opportunity to identify an asthma-susceptibility gene(s) in general and among Hispanics in particular. STATEMENT ON PUBLIC HEALTH RELEVANCE Little is known about the genetics of asthma in Hispanics, despite the disproportionate burden of asthma in certain Hispanic subgroups in both the U.S. and in Latin America. This proposal will utilize state-of-the-art genetic and genomic approaches to help to understand a component of the genetic regulation of total serum IgE, a critical intermediate of asthma, in general and among Hispanics in particular. (End of Abstract)