α5 Nicotinic Receptor Polymorphism amplifies cigarette smoke-induced inflammation in COPD - 09/05/26

Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death worldwide, representing a major global health burden. Cigarette smoke (CS) is the dominant risk factor for the development of COPD; however, only a subset of smokers develop the disease, suggesting that additional host-related factors, including genetic predisposition, play a pivotal role. Among the candidate genes, a single nucleotide polymorphism (SNP) in the α5 subunit of the nicotinic acetylcholine receptor (nAChR), referred to as α5SNP (rs16969968), has emerged as a strong genetic modifier of COPD risk. This variant is expressed in the majority of COPD patients and is thought to alter nAChR signaling, potentially influencing immune cell activation and inflammatory responses to cigarette smoke. The precise contribution of α5SNP to COPD pathogenesis, however, remains poorly understood. The present study aimed to determine how α5SNP modulates CS-induced inflammation and lung injury in both experimental murine models and clinical human cohorts.

To dissect the role of α5SNP in COPD pathogenesis, we generated a murine knock-in model expressing wild-type (WT), heterozygous (HE), or homozygous (HO) α5SNP alleles. Mice from each genotype were exposed to either ambient air or whole-body CS for one or three months. Following exposure, lung function was assessed by flexivent, and histopathological analyses were performed to quantify emphysema development, airway remodeling, and inflammatory infiltration. Immune cell profiling was conducted using flow cytometry to characterize immune populations. Cytokine and chemokine expression was quantified by multiplex assays. To translate experimental findings to humans, a well-characterized COPD patient cohort was genotyped for α5SNP, and systemic inflammatory biomarkers were measured in plasma.

Cigarette smoke exposure led to impaired lung function across all genotypes, but the magnitude of injury varied according to α5SNP allele status. HE mice exhibited the most severe phenotype, with pronounced airflow limitation, increased airway remodeling, and extensive inflammatory cell infiltration compared to WT and HO counterparts. They showed heightened activation of γδ T cells and increased production of TNF-α. These effects were linked to altered nAChR signaling within macrophage. In the human cohort, α5SNP was highly prevalent among COPD patients and strongly correlated with elevated systemic markers of inflammation, including TNF-α and IL-6, as well as with more severe clinical outcomes. Together, these data provide converging evidence from both experimental and clinical settings that α5SNP amplifies inflammatory responses to cigarette smoke.

Our findings demonstrate that α5SNP significantly enhances susceptibility to CS-driven lung injury and chronic inflammation. Importantly, the heterozygous state appears to confer the higher risk, highlighting for the first time the gene-environement role in COPD pathogenesis. Given its high prevalence among COPD patients, these results underscore the potential of targeting α5SNP-related pathways as part of precision medicine approaches and thereby improve COPD management and outcomes Fig. 1 .