Published ahead of print on January 6, 2006, doi:10.1164/rccm.200509-1387OC
Am. J. Respir. Crit. Care Med., Volume 173, Number 8, April 2006, 858-864
A more recent version of this article appeared on April 15, 2006
Submitted on September 7, 2005
Accepted on January 4, 2006
Genetically Increased Antioxidative Protection and Decreased Chronic Obstructive Pulmonary Disease
Klaus Juul1, Anne Tybjaerg-Hansen2, Stefan Marklund3, Peter Lange4, and Borge G Nordestgaard5*
1 Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark,
2 Rigshospitalet, Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen City Heart Study, Bispebjerg University Hospital, Bispebjerg, Denmark,
3 Department of Clinical Chemistry, Umea University Hospital, Umea, Sweden,
4 Department of Respiratory Medicine, Hvidovre University Hospital, Hvidovre, Denmark; The Copenhagen City Heart Study, Bispebjerg University Hospital, Bispebjerg, Denmark,
5 Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark; The Copenhagen City Heart Study, Bispebjerg University Hospital, Bispebjerg, Denmark
* To whom correspondence should be addressed. E-mail: brno{at}herlevhosp.kbhamt.dk.
Rationale:
Increased oxidative stress is involved in chronic obstructive pulmonary disease (COPD); however, plasma and bronchial lining fluid contains the antioxidant extracellular superoxide dismutase. Approximately 2% of white individuals carry the R213G polymorphism in the gene encoding extracellular superoxide dismutase, which increases plasma extracellular superoxide dismutase 10-fold and presumably also renders bronchial lining fluid high in extracellular superoxide dismutase.
Objective:
We tested the hypothesis that R213G reduces the risk of COPD.
Methods:
We studied cross-sectionally and prospectively (during 24 years) 9,258 individuals from the Danish general population genotyped for R213G.
Measurements:
We determined plasma extracellular superoxide dismutase concentration, pulmonary function and COPD diagnosed by means of spirometry or through national hospitalization and death registers.
Main results:
In the general population, 97.7% were non-carriers, 2.4% were heterozygotes and 0.02% were homozygotes. Among R213G non-carriers, extracellular superoxide dismutase plasma concentration was 148±52 and 142±43 ng/mL (mean±SD) in individuals with and without COPD (Student's t-test, p=0.02). Among heterozygotes, corresponding concentrations were 1,665±498 ng/mL and 1,256±379 (p<0.001). The adjusted odds ratio for spirometrically diagnosed COPD in heterozygotes versus non-carriers was 0.5 (95% confidence interval: 0.3-0.9). After stratification, the equivalent adjusted odds ratio was 1.5 (0.3-6.6) among non-smokers and 0.4 (0.2-0.8) among smokers (p-value for interaction=0.10). The adjusted hazard ratio for COPD hospitalization or death during follow-up in heterozygotes versus non-carriers was 0.3 (0.1-0.8).
Conclusions:
Extracellular superoxide dismutase R213G heterozygosity protects against development of COPD in the Danish general population. This was observed in smokers, but not in non-smokers.
Key words: COPD, genetics, smoking, epidemiology
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