Revez J A, Matheson M C, Hui J, Baltic S, James A, Upham J W, Dharmage S, Thompson P J, Martin N G, Hopper J L, Ferreira M A R
QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.
Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Vic., Australia.
Allergy. 2016 Jul;71(7):1020-30. doi: 10.1111/all.12869. Epub 2016 Mar 24.
Functional variants in the interleukin-6 receptor gene (IL6R) are associated with asthma risk. We hypothesized that genes co-expressed with IL6R might also be regulated by genetic polymorphisms that are associated with asthma risk. The aim of this study was to identify such genes.
To identify genes whose expression was correlated with that of IL6R, 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 IL6R were then screened for nearby single nucleotide polymorphisms (SNPs) that were significantly associated with both variation in gene expression levels (eSNPs) and asthma risk.
We identified 90 genes with expression levels correlated with those of IL6R 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 eSNPs for four known (IL18R1, IL18RAP, BCL6, and STAT6) and one putative novel asthma risk gene, stomatin-like protein 2 (STOML2). The expression of STOML2 was negatively correlated with IL6R, while eSNPs that increased the expression of STOML2 were associated with an increased asthma risk.
The expression of STOML2, a gene that plays a key role in mitochondrial function and T-cell activation, is associated with both IL-6 signaling and asthma risk.
白细胞介素6受体基因（IL6R）中的功能变异与哮喘风险相关。我们推测与IL6R共表达的基因可能也受与哮喘风险相关的基因多态性调控。本研究旨在鉴定此类基因。
为鉴定其表达与IL6R相关的基因，我们分析了由Geuvadis联盟生成的373个人类淋巴母细胞系以及由分化图谱门户（DMAP）项目生成的38种造血细胞类型的基因表达水平。然后筛选与IL6R相关的基因，寻找与基因表达水平变异（表达数量性状基因座，eSNPs）及哮喘风险均显著相关的附近单核苷酸多态性（SNPs）。
我们鉴定出90个基因，其表达水平与IL6R相关，且在已发表的哮喘全基因组关联研究（GWAS，N = 20776）中也有与疾病风险相关的附近eSNP。对于16个（18%）基因，eSNP与哮喘风险之间的关联在另一项独立发表的哮喘GWAS（N = 27378）中以相同的效应方向得到重复。在顶级重复关联（错误发现率<0.05）中，有四个已知基因（IL18R1、IL18RAP、BCL6和STAT6）以及一个推测的新型哮喘风险基因——类stomatin蛋白2（STOML2）的eSNPs。STOML2的表达与IL6R呈负相关，而增加STOML2表达的eSNPs与哮喘风险增加相关。
STOML2基因在线粒体功能和T细胞活化中起关键作用，其表达与IL-6信号传导及哮喘风险均相关。
