Abstract
The Trans-National Asthma Genetic Consortium (TAGC) identified 878 SNPs associated with asthma. We hypothesized that those SNPs affect asthma risk by regulating gene expression in airway epithelium, and conducted expression quantitative trait loci (eQTL) and mediation analyses to identify direct associations between the SNPs and expression levels of cis-genes (within 1 Mb) in nasal (airway) epithelium from Puerto Rican children with (n=228) and without (n=241) asthma. We then tested whether genes whose expression is associated with TAGC SNPs are differentially expressed (DE) in atopic asthma. We identified 1,150 direct associations between 418 TAGC SNPs and the expression of 55 cis-genes. Most SNPs regulate distant cis-genes (average distance ~200 kb). Our mediation analysis showed that 4,571 (89.2%) of 5,119 (direct and indirect) SNP-gene expression associations are mediated by methylation. Of 114 genes whose expression is associated with TAGC SNPs, 54 are DE in atopic asthma, including novel and previously reported genes. In an independent cohort of 72 African American children, 50 of the 54 DE genes were available, and 21 (42%) were also DE in atopic asthma. Thus, we show that many TAGC SNPs are associated with expression of distant cis-genes in airway epithelium, and that this is predominantly mediated by DNA methylation. Moreover, nearly half of the genes whose expression in airway epithelium is associated with TAGC SNPs are also DE in atopic asthma. Our findings support a key role of regulation of airway epithelial gene expression on atopic asthma in children.