Identification of STOML2 as a putative novel asthma risk gene associated with IL6R

Abstract Background Functional variants in the interleukin‐6 receptor gene ( IL 6R ) are associated with asthma risk. We hypothesized that genes co‐expressed with IL 6R might also be regulated by genetic polymorphisms that are associated with asthma risk. The aim of this study was to identify such genes. Methods To identify genes whose expression was correlated with that of IL 6R , we analyzed gene expression levels generated for 373 human lymphoblastoid cell lines by the Geuvadis consortium and for 38 hematopoietic cell types by the Differentiation Map Portal ( DMAP ) project. Genes correlated with IL 6R were then screened for nearby single nucleotide polymorphisms ( SNP s) that were significantly associated with both variation in gene expression levels ( eSNP s) and asthma risk. Results We identified 90 genes with expression levels correlated with those of IL 6R and that also had a nearby eSNP associated with disease risk in a published asthma GWAS ( N = 20 776). For 16 (18%) genes, the association between the eSNP and asthma risk replicated with the same direction of effect in a further independent published asthma GWAS ( N = 27 378). Among the top replicated associations ( FDR < 0.05) were eSNP s for four known ( IL 18R1 , IL 18 RAP , BCL 6 , and STAT 6 ) and one putative novel asthma risk gene, stomatin‐like protein 2 ( STOML 2 ). The expression of STOML 2 was negatively correlated with IL 6R , while eSNP s that increased the expression of STOML 2 were associated with an increased asthma risk. Conclusion The expression of STOML 2 , a gene that plays a key role in mitochondrial function and T‐cell activation, is associated with both IL ‐6 signaling and asthma risk.