Superoxide dismutase 3 polymorphism associated with reduced lung function in two large populations.
BACKGROUND
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.


OBJECTIVE
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.


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 FEV(1) % 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.
Dahl
Morten
M
Department of Clinical Biochemistry and Copenhagen General Population Study, Herlev Hospital and Copenhagen University Hospital, Copenhagen, Denmark.
Bowler
Russell P
RP
Juul
Klaus
K
Crapo
James D
JD
Levy
Samuel
S
Nordestgaard
Børge G
BG
D003430:Cross-Sectional Studies; D003718:Denmark; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000503:physiopathology; D015203:Reproducibility of Results; D012129:Respiratory Function Tests / Q000379:methods; D013147:Spirometry / Q000379:methods; D013482:Superoxide Dismutase / Q000235:genetics*; D014797:Vital Capacity
D005819:Genetic Markers; C441642:SOD3 protein, human; D013482:Superoxide Dismutase