Sex-differences in airway transcriptomic signatures in asthma.

To understand sex differences in asthma (A) across the ages, we assessed sex-differences in bronchial epithelial cells RNAseq data from 3 cohorts (SARP 3, GSE85567, GSE201955) and combined the results in a meta-analysis. We stratified our analysis by age (1: ≤50 years, n=165 Females (F), 88 Males (M); 2: >50 years, n=70 F, 29 M) to account for menopause. Differentially expressed genes (DEGs) were identified using DESeq2 for asthmatics and controls (C) separately within each age strata. DEGs in F vs. M with A but not in C were identified with a Z- score interaction test and were used for pathway enrichment analysis (PEA). We adjusted for multiple testing with the Benjamini-Hochberg method. 52 DEGs were identified in F vs. M age ≤50 with A, but not in C. Similarly, 111 DEGs were identified in F vs. M age >50 with A but not in C (Figure 1). Of the significant DEGs in both age strata, 15 genes overlapped: ALOX5, AOC3, COLEC12, FCGR3A, FFAR4, FN1, HK3, LSAMP, MCEMP1, OSCAR, PCOLCE2, PECAM1, SLC19A3, SLC47A1, and STAC. In both age groups, the differential PEA were related to ciliopathies, mitochondrial function, the innate and adaptive immune system, and leukotriene (LT) synthesis pathway. Our findings suggest that sex influences the LT biologic pathway, where the suppression of LT synthesis - mediated by ALOX-5 - by androgens in males, may impact response to therapy. This explains previously reported greater responses to LT inhibition in women. erj;66/suppl_69/PA6342/F1 F1 F1