PO.PS01.07 · 人群科学
遗传与免疫信号的分歧是哮喘与癌症之间负相关的基础
Genetic and immune signaling divergence underlies the inverse associationbetween asthma and cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
在流行病学研究中一致观察到哮喘与几种癌症类型之间存在负相关,然而这一关系背后的分子机制仍不清楚。为填补这一空白,我们进行了全面的遗传和功能分析,以识别可能促成这种保护性关联的变异、基因和免疫信号通路。从文献验证的全基因组关联研究中,我们汇编了246个哮喘相关SNP,并识别出14个同样与癌症风险显著相关的变异。值得注意的是,其中11个SNP表现出方向逆转,即哮喘风险等位基因与癌症风险降低相关,尤其是在胶质瘤和结直肠癌中。单倍型分析进一步揭示了19个对哮喘和癌症易感性表现出相反效应的基因。其中,IL-9、TLR1、SMAD7、LPP、IL-7R和HLA-DQB1在哮喘组织与多种癌症类型之间还表现出相反的基因表达模式,表明在转录水平上存在功能对立。使用Ingenuity通路分析进行的通路富集识别出Th1/Th2免疫轴调控和糖皮质激素受体信号是驱动这一生物学分歧的核心网络。具体而言,在哮喘中上调、增强Th2主导的IgE介导免疫应答的基因,与癌症背景下增强的免疫监视和T细胞细胞毒性激活相关联,提示了肿瘤起始和进展减少的机制基础。与此同时,糖皮质激素受体亚型调控作为一个潜在调节因子出现,将哮喘治疗与癌症易感性联系起来。总之,这些结果提供了首个整合的遗传、转录组和通路层面的证据,支持哮喘-癌症负相关的因果免疫学框架。这项工作凸显了变态反应性炎症与肿瘤免疫交界处的新分子靶点,并提示了将哮喘中使用的免疫调节策略重新用于指导癌症预防和治疗的机会。
查看英文原文 English abstract
An inverse association between asthma and several cancer types has been consistently observed across epidemiologic studies, yet the molecular mechanisms underlying this relationship remain unclear. To address this gap, we conducted a comprehensive genetic and functional analysis to identify variants, genes, and immune signaling pathways that may contribute to this protective association. From literature-validated genome-wide association studies, we compiled 246 asthma-associated SNPs and identified 14 variants that were also significantly associated with cancer risk. Notably, 11 of these SNPs demonstrated reversal directionality, where the asthma risk allele was associated with reduced cancer risk, particularly in glioma and colorectal cancer. Haplotype analysis further revealed 19 genes exhibiting diametric effects on asthma and cancer susceptibility. Among these, IL-9, TLR1, SMAD7, LPP, IL-7R, and HLA-DQB1 also showed inverse gene expression patterns between asthma tissues and multiple cancer types, indicating functional opposition at the transcriptional level. Pathway enrichment using Ingenuity Pathway Analysis identified Th1/Th2 immune axis regulation and glucocorticoid receptor signaling as central networks driving this biological divergence. Specifically, genes upregulated in asthma that elevate Th2-dominant IgE-mediated immune responses were linked to enhanced immunosurveillance and T-cell cytotoxic activation in cancer contexts, suggesting a mechanistic basis for reduced tumor initiation and progression. Meanwhile, glucocorticoid receptor isoform regulation emerged as a potential modulator linking asthma treatment to cancer vulnerability. Together, these results provide the first integrated genetic, transcriptomic, and pathway-level evidence supporting a causal immunologic framework for the inverse asthma-cancer association. This work highlights new molecular targets at the interface of allergic inflammation and tumor immunity and suggests opportunities for therapeutic repurposing of immune-modulating strategies used in asthma to inform cancer prevention and treatment.
利益披露 Disclosure
K. Garofalo, None..
Y. Wang, None..
P. Cook, None..
Y. Guo, None..
Y. Zhu, None.