Clinical implication of transcriptional dysregulation in the SHH-GLI pathway involving the GLI1 rs61739569 (T>C) variant toward chronic obstructive pulmonary disease (COPD) in North Indians.

Abstract

Background: Chronic obstructive pulmonary disease (COPD) ranks among the leading causes of morbidity and mortality globally. Genomic susceptibility factors are acknowledged as critical modulators of disease variability and progression. The Sonic Hedgehog (SHH) pathway regulates epithelial tissue healing, mucin synthesis, and airway remodeling. GLI1 polymorphic variants may influence the manifestations of COPD.

Methodology: A case-control study was conducted, involving 500 patients with COPD and 500 controls from the North Indian population. We genotyped two GLI1 polymorphisms (rs61739569 (T>C) and rs2228226 (G>C). Logistic regression models were applied to examine the associations between COPD susceptibility and clinical features.

Results: rs61739569 and rs2228226 show no association with an increased risk of COPD overall. Nonetheless, rs61739569 exhibited significant phenotype-specific correlations: individuals possessing the CC genotype demonstrated a markedly elevated risk of chronic cough, sputum production, and exacerbations, while displaying a diminished risk of dyspnea and activity limitation.

Conclusion: Variations in GLI1 may influence the symptoms of COPD, rather than the overall likelihood of developing COPD. The rs61739569 is particularly applicable to mucus-dominant phenotypes, such as those resembling chronic bronchitis. This study suggests that GLI1 signaling exhibits context-dependent functional significance in COPD.