TY - JOUR
T1 - Superoxide Dismutase 3 Polymorphism Associated with Reduced Lung Function in Two Large Populations
AU - Dahl, Morten
AU - Bowler, Russell P
AU - Juul, Klaus
AU - Crapo, James D
AU - Levy, Samuel
AU - Nordestgaard, Børge G
N1 - Times Cited: 0ArticleEnglishNordestgaard, B. GCopenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev Ringvej 75, DK-2730 Herlev, DenmarkCited References Count: 42368HGAMER THORACIC SOC1740 BROADWAY, NEW YORK, NY 10019-4374 USANEW YORK
PY - 2008
Y1 - 2008
N2 - Rationale: Superoxide dismutase (SOD) 3 inhibits oxidative fragmentation of lung matrix components Collagen 1, 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
Udgivelsesdato: 2008/11/1
AB - Rationale: Superoxide dismutase (SOD) 3 inhibits oxidative fragmentation of lung matrix components Collagen 1, 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
Udgivelsesdato: 2008/11/1
KW - Cross-Sectional Studies
KW - Denmark
KW - Female
KW - Follow-Up Studies
KW - Genetic Markers
KW - Humans
KW - Lung
KW - Male
KW - Middle Aged
KW - Oxidative Stress
KW - Polymorphism, Genetic
KW - Predictive Value of Tests
KW - Proportional Hazards Models
KW - Prospective Studies
KW - Pulmonary Disease, Chronic Obstructive
KW - Reproducibility of Results
KW - Respiratory Function Tests
KW - Spirometry
KW - Superoxide Dismutase
KW - Vital Capacity
U2 - 10.1164/rccm.200804-549OC
DO - 10.1164/rccm.200804-549OC
M3 - Journal article
C2 - 18703790
SN - 1073-449X
VL - 178
SP - 906
EP - 912
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
IS - 9
ER -