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