The Impact of Biological Sex on Asthma Outcomes

Abstract Asthma affects prepubescent males more than females, but a sex-switch occurs after puberty and asthma is more common in females than males. This research proposal investigates the effect of sex and sex hormones on asthma severity. The long-term goal of our studies is to identify sex related differences in genetic risks and biological pathways of severe asthma. Our analyses of well characterized asthma cohorts and large databases reveal that severe asthma exhibits a bimodal peak in prepubescent males and middle-aged females [3], which pointes to sex hormones in mechanisms of asthma severity. Preliminary data of sex hormone levels from females participants enrolled in SARP 1-3 (2001-2018) showed that FEV1 (%) correlated negatively with estradiol, but positively with progesterone. Additionally, the adrenal androgen dehydro-epiandrosterone sulfate (DHEA-S) correlated positively with FEV1 (%) in both female and male SARP participants, whereas testosterone levels correlated with FEV1 (%) in males but not in females. Our data also suggest that sex hormones modulate airway inflammation through their effect on sex steroids receptors (SSRs). Gene expression data from bronchial epithelial cells obtained by bronchoscopy from 128 SARP 3 participants with asthma revealed significant correlation between estrogen receptors 1 and 2 (ESR1 and ESR2) gene expression and inflammatory cytokine receptors (IL6R, IL4R, IL5RA, and IL13RA1) gene expression. Our preliminary analyses of SARP1-2 BEC microarray data (n= 72 females, 32 males) showed sex-specific differential targeting of groups of interacting genes representing particular biological functions (mitochondrial function in females with asthma and interferon signaling in males). These data suggest that sex and sex hormones play an important role in the clinical manifestations of asthma genetic risk variants. Based on these cumulative findings, we hypothesize that sex and sex hormones influence immune system activation and airway inflammation to drive asthma phenotypes and progression differentially in males and females across the lifespan. In aim 1 we evaluate how sex hormone serum concentrations and SSRs expression in blood, upper, and lower airway cells determine T2 inflammation and asthma severity in males and females. In aim 2 we identify the sex-specific genetic effects of loci across the genome on asthma risk and severity resulting from DNA variant interactions with hormone and nuclear receptor expression. In aim 3, we will assess whether sexual dimorphism of asthma is related to a higher order of gene interactions and variation in sex-specific configurations in gene regulatory networks. The proposed studies have the potential to define key hormonal and genomic drivers of asthma risk and severity over the lifespan in male and female individuals and address a large knowledge gap of how sex and sex hormones modify asthma risk and severity. Future studies will aim, using this data, to identify personalized, hormone-based risk stratification and treatment approaches for male and female individuals with asthma.