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Superoxide Dismutase 3 Polymorphism Associated with Reduced Lung Function in Two Large Populations

¹ Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev Hospital and Copenhagen University Hospital, Copenhagen, Denmark; ² Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado; ³ J. Craig Venter Institute, Rockville, Maryland; and ⁴ Copenhagen City Heart Study, Bispebjerg Hospital and Copenhagen University Hospital, Copenhagen, Denmark

Correspondence and requests for reprints should be addressed to Børge G. Nordestgaard, M.D., D.M.Sc., Professor and Chief Physician, Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail: brno{at}heh.regionh.dk

Rationale: Superoxide dismutase (SOD) 3 inhibits oxidative fragmentation of lung matrix components collagen I, hyaluronan, and heparan sulfate. Inherited change in SOD3 expression or function could affect lung matrix homeostasis and influence pulmonary function.

Objectives: To identify novel SOD3 polymorphisms that are associated with lung function or chronic obstructive pulmonary disease (COPD).

Methods: Resequencing of 182 individuals identified two novel polymorphisms, E1 (rs8192287) and I1 (rs8192288), in a conserved region of the SOD3 gene of potential relationship to lung function. We next genotyped 9,093 individuals from the Copenhagen City Heart Study for the polymorphisms and recorded spirometry, and admissions and deaths due to COPD during 26-year follow-up. Finally, we validated our findings in a cross-sectional analysis of 35,635 individuals from the Copenhagen General Population Study.

Measurements and Main Results: Genotyping the Copenhagen City Heart Study identified 35 E1/I1 homozygotes, 1,050 heterozygotes, and 8,008 noncarriers (Hardy-Weinberg equilibrium: P = 0.93). Using quadruple lung function measurements, we found that E1/I1 homozygotes had 7% lower FVC % predicted (P = 0.006) and 4% lower FEV₁ % predicted (P = 0.12) compared with noncarriers. In the Copenhagen General Population Study, E1/I1 homozygotes also had lower FVC % predicted than noncarriers (P = 0.03), confirming an association between E1/I1 genotype and reduced lung function. E1/I1 homozygotes had adjusted hazard ratios for COPD hospitalization and COPD mortality of 2.5 (95% confidence interval, 1.0–5.9) and 3.7 (95% confidence interval, 0.9–15), respectively; the results were independent of influence from the R213G allele of the SOD3 gene.

Conclusions: We identified two novel polymorphisms in a conserved region of the SOD3 gene and show that individuals that are homozygous for these polymorphisms have reduced FVC % predicted in two large, population-based studies.

Key Words: superoxide dismutase 3 • genetics • chronic obstructive pulmonary disease • oxidative stress

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Extracellular superoxide dismutase (EC-SOD) inhibits oxidative fragmentation of lung matrix components collagen I, hyaluronan, and heparan sulfate. Inherited change in EC-SOD expression or function could affect lung matrix homeostasis and influence pulmonary function. What This Study Adds to the Field We identified two novel polymorphisms in a conserved region of the EC-SOD gene and show that individuals that are homozygous for these polymorphisms have reduced FVC % predicted in two large, population-based studies.