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

VL - 178

SP - 906

EP - 912

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 9

ER -