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Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation in the lung airway. Cigarette smoking is the most important risk factor for COPD.1 Heme oxygenase-1 (HO-1) is a key enzyme in heme metabolism and provides cytoprotection against oxidants in cigarette smoke.2 A (GT)n dinucleotide repeat in the human HO-1 promoter shows length polymorphism which is categorised into three groups: S-allele (<27 GT repeats), M-allele (27–32 GT repeats), and L-allele (⩾33 GT repeats).3 The L-allele was found to be associated with reduced HO-1 inducibility and susceptibility to pulmonary emphysema in a case-control study of Japanese male smokers.3 Conversely, He et al4 reported that HO-1 polymorphism was not related to a rapid decline in lung function in a prospective study of white smokers.
To evaluate the role of HO-1 polymorphism in the decline in lung function in Japanese subjects, 101 Japanese male ex-smokers with mild to severe COPD (forced expiratory volume in 1 second (FEV1) 40–90% predicted and FEV1/FVC <70%) were enrolled from January 2000 to December 2001 and HO-1 polymorphism was checked by PCR with peripheral blood DNA. Spirometric tests were performed at the beginning of the study and annually for 3 years. All participants sustained smoking cessation and were treated with bronchodilators including β2 agonists and/or anticholinergic agents but not the long acting anticholinergic tiotropium. Rapid decliners are defined as subjects with a mean annual decrease in FEV1 of ⩾3.0% predicted,1 whereas non-rapid decliners were subjects with a mean annual decline in FEV1 of <3.0% predicted. Patients with active pneumonia, bronchial asthma, and malignant disease were excluded.
There were 28 individuals with the L-allele (L-allele carriers) and 73 without the L-allele (non-L-allele carriers). The baseline characteristics of L-allele carriers and non-carriers did not differ (table 1). At the end of the follow up period there were 25 subjects with a rapid decline in lung function and 76 non-rapid decliners. The mean annual decline in FEV1 % predicted in L-allele carriers was significantly larger than in non-carriers (mean (SE) 2.74 (1.22)% per year v −0.57 (0.89)% per year, p = 0.044, unpaired t test, table 1). The proportion of rapid decliners was significantly higher among L-allele carriers than in non-L-allele carriers (12 (42.9%) v 13 (17.8%), p = 0.009, χ2 test, table 1). Furthermore, the factors associated with a rapid decline in lung function were calculated by multivariate logistic regression analysis to adjust for potential risk factors including age, smoking status (pack-years), baseline FEV1 predicted, and L-allele carrier status. As a result, the adjusted odds ratio of L-allele carrier status for rapid decliners was 3.9 (95% CI 1.4 to 10.6), p = 0.009 (12 (48.9%) in rapid decliners v 16 (21.1%) in non-rapid decliners). Other factors were not significantly associated with a rapid decline in lung function.
The results of this study suggest that polymorphism of the HO-1 promoter gene may be associated with the rate of decline in lung function in Japanese male ex-smokers. A larger study is needed to confirm this result. Although the reason for the discrepancy between the results of our study and that of He et al4 is not clear, it might result from the difference in ethnic background of the participants. Since the susceptibility to COPD and/or decline in lung function could be influenced by a number of genetic and environmental factors, different polymorphisms in different ethnic groups may cause the same COPD phenotype. It is therefore important to confirm the associations of polymorphisms in each population. The L-allele carrier of the HO-1 promoter gene in Japanese men is significantly associated with risks of developing lung adenocarcinoma,5 pulmonary emphysema,3 and less longevity.2 Modification of HO-1 gene expression may offer a new target for therapeutic intervention in lung disease in the Japanese population.
The authors thank Mr Grant Crittenden for correcting the English.
Dr Nakayama was partly supported by a grant from the Japanese Foundation for Aging and Health of the Ministry of Welfare and Labor of the Japanese government. Dr Yasuda was partly supported by a Grant-In-Aid for Scientific Research from the Ministry of Education, Science and Culture (17790524) of the Japanese government. Dr Yamaya was partly supported by a Grant-In-Aid for Scientific Research from the Ministry of Education, Science and Culture (16590732) and the Ministry of Welfare and Labor of the Japanese government.
Competing interests: none declared.
The first two authors contributed equally to this work.
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