Background and objective: Cathepsin S is involved in the pathogenesis of COPD in murine models overexpressing interferon (IFN)-γ and IL-13. It is widely accepted that genetic factors partly influence susceptibility to COPD; however, the association of genetic polymorphisms in the cathepsin S gene with COPD has not been reported previously. In this study, functional polymorphisms in the 5′-flanking region of the human cathepsin S gene were identified and their association with COPD phenotypes was investigated. Methods: Genetic polymorphisms were detected by single strand conformation polymorphism analysis and direct sequencing. Genotypes and haplotypes were determined using amplification refractory mutation systems and single strand conformation polymorphism analysis. A promoter-reporter assay was used to compare transcriptional activities between the haplotypes on stimulation with IFN-γ. Haplotype analysis was performed on 204 smoking and 104 non-smoking Japanese subjects. Results: Four novel polymorphisms were detected in the 5′-flanking region and three major haplotypes were identified. The haplotypes were associated with distinct promoter activities on stimulation with IFN-γ and there was a trend indicating that higher transcriptional activity was linked to less pulmonary emphysema. Conclusion: Novel functional polymorphisms were identified in the cathepsin S gene, which has a possible association with pulmonary emphysema in the Japanese population.
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