Genetics of epithelial genes in childhood asthma

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

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Abstract

Asthma is a major public health problem affecting 15 million people in the United States alone. Although the[unreadable] etiologic factors that lead to the development of asthma remain largely undefined, it is clear that asthma and[unreadable] other allergic disorders have a strong genetic predisposition. More than 19 different chromosomal regions[unreadable] have been linked to asthma or its related phenotypes in genome-wide scans, but the relevant genes remain[unreadable] largely unknown. Recently, several studies have implicated epithelial cells as key participants in the[unreadable] development of allergic inflammation. We recently utilized microarray technology to identify genes that are[unreadable] consistently upregulated in nasal epithelial cells from children with asthma. There were 161 genes that were[unreadable] consistently up- or down-regulated at least 3 fold (p<0.01) in at least 3 out of 4 individuals with asthma.[unreadable] Dramatic differences in prevalence of asthma across human subpopulations have been revealed, especially[unreadable] between Caucasians and the Han Chinese. From the 161 genes identified from our microarray approach, we[unreadable] identified 14 known genes that manifested very great allele frequency difference (FST > 0.25) between[unreadable] Caucasians and Han Chinese using data from the public HapMap database. This[unreadable] subset of genes may have been targeted by natural selection causing alleles to be favored in one but not[unreadable] both of the populations. Further investigation of these genes revealed that 6 of these genes are located in[unreadable] chromosomal regions that have been linked to asthma/atopy phenotypes and have been shown to either be[unreadable] regulated during allergic inflammation and/or to regulate release of Th2 cytokines including IL-13, yet none of[unreadable] these genes have been studied as potential candidate genes for asthma. In this application, we propose a[unreadable] case-control design study with 3 aims to address the following hypothesis: One or more of the identified[unreadable] allergy-driven epithelial genes will be significantly associated with phenotypic patterns of allergic[unreadable] sensitization and/or asthma in children and that the genetic contribution of these alleles is modified by[unreadable] gene:gene interactions with SNPs in IL13, IL4 or IL4RA, and/or by gene:environment interactions of pet or[unreadable] tobacco smoke exposure in the home. The public health impact of this study will be significant. Through the[unreadable] results of this study, we will be able provide information regarding the relevant epithelial genes with regard to[unreadable] childhood asthma health and genetic biomarkers of childhood asthma.