Common functional polymorphisms in the cathepsin S promoter in Japanese subjects: possible contribution to pulmonary emphysema.
OBJECTIVE
Cathepsin S is involved in the pathogenesis of COPD in murine models overexpressing interferon (IFN)-gamma 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-gamma. 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-gamma and there was a trend indicating that higher transcriptional activity was linked to less pulmonary emphysema.


CONCLUSIONS
Novel functional polymorphisms were identified in the cathepsin S gene, which has a possible association with pulmonary emphysema in the Japanese population.
Minematsu
Naoto
N
Division of Pulmonary Medicine, Department of Medicine, Keio University, Tokyo, Japan.
Nakamura
Hidetoshi
H
Furuuchi
Momoyo
M
Nakajima
Takahiro
T
Takahashi
Saeko
S
Tsujimura
Shuko
S
Tateno
Hiroki
H
Ishizaka
Akitoshi
A
D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D002403:Cathepsins / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D007564:Japan; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology / Q000235:genetics; D011656:Pulmonary Emphysema / Q000235:genetics*; D012907:Smoking / Q000453:epidemiology / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
D007371:Interferon-gamma; D002403:Cathepsins; C028217:cathepsin S