Association of GCLC rs600033 polymorphism with acute exacerbation phenotypes in COPD

Purpose: Chronic Obstructive Pulmonary Disease (COPD) is characterized by an imbalance between oxidative stress and antioxidant defense. Cellular senescence exacerbates this imbalance by impairing glutathione (GSH) synthesis, in which the glutamate-cysteine ligase catalytic subunit (GCLC) is the rate-limiting enzyme. This exploratory, hypothesis-generating study evaluated the association between the GCLC rs600033 G>C polymorphism and acute exacerbations of COPD (AECOPD) in a Turkish cohort.Materials and Methods: A total of 117 COPD patients (59 stable, 58 with acute exacerbations) and 115 healthy controls were included. Genotype and allele frequencies were compared between groups, and multivariable models adjusting for age, sex, smoking, and FEV1 assessed exacerbation risk; p-values were corrected for multiple testing.Results: No significant association was found between rs600033 G>C and overall COPD susceptibility, nor between stable COPD and AECOPD. The CC genotype was nominally more frequent in healthy controls than in AECOPD patients (OR=2.28, 95% CI: 1.04-5.00), but this association did not remain significant after correction for multiple testing. Predicted AECOPD probability increased with age, but the age × genotype interaction was not significant, and neither age nor genotype remained significant in the adjusted model. Adding genotype did not significantly improve model discrimination.Conclusion: The GCLC rs600033 polymorphism showed only a nominal, unadjusted association with AECOPD that did not withstand correction for multiple testing or covariate adjustment. These exploratory findings do not support an independent role for this polymorphism in COPD exacerbation risk and require validation in larger cohorts.