Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
Department of Biology, University of Northern Iowa, Cedar Falls, IA, USA.
Hum Mol Genet. 2019 Aug 1;28(15):2600-2614. doi: 10.1093/hmg/ddz074.
Global gene-expression analysis has shown remarkable difference between males and females in response to exposure to many diseases. Nevertheless, gene expression studies in asthmatics have so far focused on sex-combined analysis, ignoring inherent variabilities between the sexes, which potentially drive disparities in asthma prevalence. The objectives of this study were to identify (1) sex-specific differentially expressed genes (DEGs), (2) genes that show sex-interaction effects and (3) sex-specific pathways and networks enriched in asthma risk. We analyzed 711 males and 689 females and more than 2.8 million transcripts covering 20 000 genes leveraged from five different tissues and cell types (i.e. epithelial, blood, induced sputum, T cells and lymphoblastoids). Using tissue-specific meta-analysis, we identified 439 male- and 297 female-specific DEGs in all cell types, with 32 genes in common. By linking DEGs to the genome-wide association study (GWAS) catalog and the lung and blood eQTL annotation data from GTEx, we identified four male-specific genes (FBXL7, ITPR3 and RAD51B from epithelial tissue and ALOX15 from blood) and one female-specific gene (HLA-DQA1 from epithelial tissue) that are disregulated during asthma. The hypoxia-inducible factor 1 signaling pathway was enriched only in males, and IL-17 and chemokine signaling pathways were enriched in females. The cytokine-cytokine signaling pathway was enriched in both sexes. The presence of sex-specific genes and pathways demonstrates that sex-combined analysis does not identify genes preferentially expressed in each sex in response to diseases. Linking DEG and molecular eQTLs to GWAS catalog represents an important avenue for identifying biologically and clinically relevant genes.
全球基因表达分析表明，男性和女性在对许多疾病的暴露反应方面存在显著差异。然而，迄今为止，哮喘患者的基因表达研究一直集中在性别合并分析上，忽略了性别之间固有的变异性，这可能导致哮喘患病率的差异。本研究的目的是确定（1）性别特异性差异表达基因（DEGs），（2）表现出性别相互作用效应的基因，以及（3）哮喘风险中富集的性别特异性途径和网络。我们分析了 711 名男性和 689 名女性以及来自五个不同组织和细胞类型（即上皮、血液、诱导痰、T 细胞和淋巴母细胞）的 20000 多个基因的 280 多万个转录本。使用组织特异性荟萃分析，我们在所有细胞类型中鉴定了 439 个男性特异性和 297 个女性特异性 DEGs，其中有 32 个基因是共同的。通过将 DEGs 与全基因组关联研究（GWAS）目录以及来自 GTEx 的肺和血液 eQTL 注释数据联系起来，我们鉴定了四个男性特异性基因（上皮组织中的 FBXL7、ITPR3 和 RAD51B 以及血液中的 ALOX15）和一个女性特异性基因（上皮组织中的 HLA-DQA1），这些基因在哮喘期间失调。缺氧诱导因子 1 信号通路仅在男性中富集，IL-17 和趋化因子信号通路在女性中富集。细胞因子-细胞因子信号通路在两性中均有富集。性别特异性基因和途径的存在表明，性别合并分析不能识别疾病反应中每个性别优先表达的基因。将 DEG 和分子 eQTL 与 GWAS 目录联系起来，代表了识别具有生物学和临床相关性的基因的重要途径。
