The CHRNA5 rs16969968 variant is associated with MMP-9 expression and inflammatory signaling in COPD in a West Bengal population, India.

Background: Host genetic variation plays a critical role in shaping inflammatory responses to chronic environmental exposure in Chronic Obstructive Pulmonary Disease (COPD). The non-synonymous CHRNA5 polymorphism rs16969968 (G>A; D398N) has been associated with nicotine dependence; however, its immunomodulatory relevance in COPD remains insufficiently explored. Objectives: To investigate the association of the CHRNA5 rs16969968 polymorphism with COPD susceptibility and its relationship with inflammatory protease expression and cholinergic signaling pathways in a West Bengal population. Methods: We enrolled 412 COPD patients and 390 controls (41-80 years). Lung function was assessed by spirometry. Genotyping was performed using the PCR-RFLP method. CHRNA5 and MMP9 mRNA expression levels were quantified by qRT-PCR, and CHRNA5 protein expression was assessed via Western blot; BALF MMP-9 levels were measured by ELISA. Computational tools were used to predict the potential structural and functional effects of the variant. Results: The rs16969968 AA genotype was significantly enriched among COPD patients and was associated with reduced pulmonary function in smokers. Carriers of the risk genotype reported lower CHRNA5 transcript and protein expression levels along with higher MMP-9 expression compared with other genotypes. In-silico analyses also predicted that the variant D398N likely to exert subtle functional effects on α5 nicotinic acetylcholine receptor subunit. Conclusion: The findings suggest that the CHRNA5 rs16969968 variant is associated with altered cholinergic signaling and increased MMP-9 expression in COPD. These observations support a potential role for CHRNA5-related inflammatory pathways in COPD susceptibility and tissue remodeling. However, the observed associations require further functional and mechanistic validation.