Gender and Asthma

摘要 哮喘对男孩的影响比女孩更大，但性别转换发生在青春期之后，哮喘在 女人比男人多。这项研究计划研究性和性激素对哮喘严重程度的影响。 我们研究的长期目标是确定与性别有关的遗传风险差异和生物途径 严重的哮喘。我们对具有良好特征的哮喘队列和大型数据库的分析表明，严重的 哮喘在年轻男孩和中年女性中呈双峰型[3]，这表明哮喘患者体内性激素水平 哮喘严重程度的机制。参加SARP1-3的女性性激素水平的初步数据 (2001-2018)FEV1(%)与雌二醇呈负相关，与孕酮呈正相关。 此外，肾上腺雄激素硫酸脱氢表雄酮(脱氢表雄酮-S)与FEV1呈正相关 在女性和男性中，睾酮水平与FEV1(%)相关，而在女性中则不相关。我们的数据也 提示性激素通过对性类固醇受体(SSR)的作用调节呼吸道炎症。 128名SARP3参与者支气管镜检查获得的支气管上皮细胞基因表达数据 雌激素受体1和2(ESR1和ESR2)基因与哮喘显著相关 表达与炎性细胞因子受体(IL6R、IL4R、IL5RA、IL13RA1)基因表达。我们的 对SARP1-2BEC微阵列数据(n=72名女性，32名男性)的初步分析显示，性别差异- 靶向代表特定生物功能的相互作用的基因组(线粒体功能 女性和男性体内的干扰素信号)。这些数据表明，性激素和性激素起着重要作用 在哮喘的临床表现中存在遗传风险变异。基于这些累积的发现，我们假设 性激素和性激素影响免疫系统激活和呼吸道炎症导致哮喘 男性和女性在一生中的表型和进展是不同的。在目标1中，我们评估如何 性激素血清浓度和血液、上、下呼吸道细胞中SSR的表达决定T2 男性和女性的炎症和哮喘严重程度。在目标2中，我们确定了基因座的性别特异性遗传效应 跨基因组研究DNA变异与激素和核的相互作用导致的哮喘风险和严重程度 受体表达。在目标3中，我们将评估哮喘的性别二型性是否与更高的阶数有关 基因调控网络中的基因相互作用和性别特异性配置的变异。建议数 研究有可能确定哮喘风险和严重程度的关键激素和基因组驱动因素。 延长男性和女性的寿命，并解决性激素和性激素如何改善哮喘的巨大知识差距 风险和严重性。未来的研究将致力于利用这些数据来识别个性化的、基于激素的风险 男性和女性的分层和治疗方法，与背景血统无关。

Abstract Asthma affects boys more than girls, but gender-switch occurs after puberty and asthma is more common in women than men. 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 young boys and middle age women [3], which pointes to sex hormones in mechanisms of asthma severity. Preliminary data of sex hormone levels from women 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 women and men, but testosterone levels correlated with FEV1 (%) in men but not in women. 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 women, 32 men) showed sex-specific differential- targeting of groups of interacting genes representing particular biological functions (mitochondrial function in women and interferon signaling in men). 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 men and women. 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 men and women 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 in men and women, irrespective of background ancestry.