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Genetically Increased Antioxidative Protection and Decreased Chronic Obstructive Pulmonary Disease

Department of Clinical Biochemistry, Herlev University Hospital, Herlev; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital; The Copenhagen City Heart Study, Bispebjerg University Hospital, Copenhagen; Department of Respiratory Medicine, Hvidovre University Hospital, Hvidovre, Denmark; and Department of Clinical Chemistry, Umeå University Hospital, Umeå, Sweden

Correspondence and requests for reprints should be addressed to Børge G. Nordestgaard, M.D., D.M.Sc., Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. 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 yr) 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, 97.5% were noncarriers, 2.4% were heterozygotes, and 0.02% were homozygotes. Among R213G noncarriers, 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 noncarriers 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 nonsmokers 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 noncarriers 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 nonsmokers.

Key Words: chronic obstructive pulmonary disease • epidemiology • genetics • smoking

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