B109-11 Gene-Environment Interaction Involving Nicotinic Receptor Favors Lung Inflammation and COPD Development

Abstract Rationale 3rd leading cause of death worldwide, Chronic obstructive pulmonary disease (COPD) remains a major health problem. It is an inflammatory pathology characterized by slow, progressive and irreversible alteration of breathing. It is mainly caused by exposure to inhaled noxious particles, such as cigarette smoke (CS). CS is the major environmental risk factor and is present in more than 80% of COPD patients. Exposure to CS leads to chronic inflammation and alteration of the immune. However less than 20% of smokers develop COPD regardless of their level of consumption suggesting the involvement of genetic factors. Among human single nucleotide polymorphisms (SNPs) associated with smoking and COPD, variants present in the CHRNA5/A3/B4 genes (coding for subunits of nicotinic receptor (nAChR)) are among the most common, particularly the α5SNP. Moreover, α5SNP is particularly present in 65% of COPD patients and its Expression in mice triggers the development of COPD-like lesions. (Nat. Comm, 2021, Cells, 2022). Hypothesis We hypothezised that α5SNP expression enhances lung susceptibility to cigarette smoke by amplifying inflammatory and kinase signalling pathways, thus contributing to COPD development and progression. Methods Wild-type (WT), heterozygous (HE), and homozygous (HO) α5SNP knock-in mice were chronically exposed to air or whole-body cigarette smoke for 1 or 3 months to model acute and chronic COPD. Lung function was assessed by FlexiVent, and bronchoalveolar lavage fluid, lungs, spleens, and blood were collected for histological and immunological analyses. Cytokine and chemokine production was quantified by ELISA, and immune cell phenotypes were characterised by flow cytometry. PamGene kinase activity profiling was used to identify signalling pathways altered by α5SNP expression and CS exposure. In a clinical COPD cohort, α5SNP genotyping and plasma biomarker analyses (TNF-α, IL-6,..) were performed to correlate genetic status with inflammation and disease severity. Results α5SNP was expressed in over 65% of COPD versus 20% in non COPD patients and strongly associated with increased systemic TNF-α and IL-6 levels. In mice, CS exposure impaired lung function across all genotypes, with HE mice exhibiting the most severe phenotype—marked airway remodelling, emphysema, and immune infiltration. PamGene analysis revealed enhanced pathway activation in HE lungs, indicating dysregulated kinase signalling. Conclusions Expression of α5SNP sensitizes the lung to cigarette smoke. Its presence in over 65% of COPD patients supports α5SNP as a potential biomarker of susceptibility and disease severity. These findings highlight a key gene-environment interaction and suggest that targeting α5SNP-related pathways may open new precision medicine strategies to prevent COPD. This abstract is funded by: Pasteur Network, IRESP, FHU respire