Identification of Sex-Specific Candidate Genes Underlying Childhood Asthma Using Integrative Transcriptomic and Mendelian Randomization Approaches

Objective This study aimed to identify key candidate genes underlying sex disparities in childhood asthma. Methods Blood gene expression datasets from children with asthma and healthy controls (GSE27011 and GSE203482) were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between asthma and normal blood samples were identified using limma package, with sex stratification. Functional enrichment analyses were performed to characterize these DEGs. Mendelian Randomization (MR) analysis was further applied to identify sex-specific causal genes. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic potential of target genes. Bioinformatics analyses were used to explore the biological functions of candidate genes. Drug prediction and molecular docking analyses were employed to further evaluate the therapeutic potential of the identified drug targets. Results We identified 74 female-specific and 112 male-specific DEGs in pediatric asthma. Functional enrichment analysis indicated that these DEGs were potentially implicated in sex-specific asthma pathogenesis. MR analysis identified 5 causal genes in females (GNG2, HAVCR2, NMUR1, AUTS2, and DTHD1) and 3 in males (CCNE1, KRT73, and NMUR1). Five genes (GNG2, HAVCR2, NMUR1, CCNE1, and KRT73) exhibited consistent differential expression patterns across both MR and transcriptomic analysis, and were thus retained as core candidates. ROC analysis validated their diagnostic potential, with the area under the curve (AUC) values all exceeding 0.7 in the GSE27011 cohort. Immune infiltration analysis further revealed a significant elevation in resting natural killer (NK) cells in female asthma patients, while male asthma samples displayed increased resting NK cells, M0 macrophages, and resting mast cells. Molecular docking analysis showed favorable binding affinity between drugs and proteins with available structural information. Conclusion By integrating transcriptome analysis with MR approaches, we identified GNG2 and NMUR1 as female-specific causal genes in childhood asthma, along with CCNE1, KRT73 as male-specific causal genes, while NMUR1 was shared between sexes. This integrative strategy may facilitate the development of precise biomarkers and therapeutic targets for childhood asthma.