Genome-wide analysis revealed sex-specific gene expression in asthmatics

Abstract

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.

Sex-specific differences in peripheral blood leukocyte transcriptional response to LPS are enriched for HLA region and X chromosome genes

“…Moreover, ours is first study of sex specific responses that used personalized HLA read alignments to generate unbiased gene expression data at these highly polymorphic loci. Previous studies of sex differences in HLA gene expression 35,[47][48][49] did not account for this potential bias, and gene expression studies that did use personalized alignments of HLA genes did not examine sex differences 50,51 . Using unbiased estimates of HLA gene expression levels and genome-wide approaches to identify sex-specific patterns, we made the novel observation of an enrichment of LPS responses exhibiting sex by treatment interactions among class I and II HLA genes compared to all autosomal genes: 47% of HLA genes showed sex by treatment interactions whereas these interactions were observed in 8% of all autosomal genes (P = 1.1 × 10 -4 ).…”

Association Between Environmental Factors and Asthma Using Mendelian Randomization: Increased Effect of Body Mass Index on Adult-Onset Moderate-to-Severe Asthma Subtypes

“…Previous epidemiological reports have suggested that the incidence and symptoms of adult asthma are higher and more severe in women than in males ( Chen et al, 2003 ; Zein and Erzurum, 2015 ). A recent study that performed sex-specific transcriptomics in 5 tissues from asthma patients also showed sexual dimorphism in asthma, including sex-specific dysregulation of genes and signaling pathways ( Gautam et al, 2019 ). Moreover, the effect of BMI on asthma is greater in female than male adults ( Chen et al, 2002 ; Guerra et al, 2002 ; Beuther and Sutherland, 2007 ).…”

NUCB2 polymorphisms are associated with an increased risk for type 2 diabetes in the Chinese population

“…The testosterone changes were also associated with the initiation of puberty regulated by the production of NUCB2/nesfatin-1 via adipose tissue and NUCB2 gastric output (33). Another possible explanation for this gender disparity could be that variations in NUCB2 could have sex-specific phenotypic effects in T2DM, as illuminated in several other diseases (34,35). But the The given P value were sex-age-adjusted in the total population, and age-adjusted in female or male subgroup.…”