Polymorphisms in the Superoxide Dismutase-3 Gene Are Associated with Emphysema in COPD

ABSTRACT

Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes. We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1), and rs1799895 (R213G)) in a case–control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n = 389) and smoking controls from the Normative Aging Study (NAS, n = 472). We examined whether the single nucleotide polymorphisms (SNPs) were associated with COPD status, lung function variables, and quantitative computed tomography (CT) measurements of emphysema and airway wall thickness. Furthermore, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n = 3061) and the Boston Early-Onset COPD Study (EOCOPD, n = 949). In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p = .029 and p = .0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p = .048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations. In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.

Keywords: :

• Chronic obstructive pulmonary disease
• Superoxide dismutase 3
• Genetic polymorphism
• Emphysema
• Genetics

ACKNOWLEDGMENTS

The authors thank Scott Weiss, Frank Speizer, Jeffrey Drazen, Hal Chapman, Leo Ginns, and Steven Mentzer for their roles in developing the Boston Early-Onset COPD Study.

Co-investigators in the NETT Genetics Ancillary Study include Joshua Benditt, Gerard Criner, Malcolm DeCamp, Philip Diaz, Mark Ginsburg, Larry Kaiser, Marcia Katz, Mark Krasna, Neil MacIntyre, Barry Make, Rob McKenna, Fernando Martinez, Zab Mosenifar, Andrew Ries, Paul Scanlon, Frank Sciurba, and James Utz.

International COPD Genetics Network (ICGN) Investigators (in addition to Drs. Lomas and Silverman): Alvar Agusti, Son Dureta Hospital and Fundación Caubet-Cimera, Palma de Mallorca, Spain; Peter M. A. Calverley, University of Liverpool, Liverpool, UK; Claudio F. Donner, Division of Pulmonary Disease, S. Maugeri Foundation, Veruno (NO), Italy; Robert D. Levy, University of British Columbia, Vancouver, Canada; Barry J. Make, National Jewish Medical and Research Centre, Denver, Colorado; Peter D. Paré, University of British Columbia, Vancouver, Canada; Stephen I. Rennard, University of Nebraska, Omaha, Nebraska; Jørgen Vestbo, Department of Cardiology and Respiratory Medicine, Hvidovre Hospital, Copenhagen, Denmark; Emiel F. M. Wouters, University Hospital Maastricht, The Netherlands.

Sources of financial support:

This work was supported by the National Institutes of Health (K08HL080242, R01HL094635, R01HL075478, R01HL084323, P01HL083069) and a grant from the Alpha-1 Foundation. The ICGN study was supported by GlaxoSmithKline. The National Emphysema Treatment Trial was supported by the National Heart, Lung, and Blood Institute (N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01HR76119), the Centers for Medicare and Medicaid Services, and the Agency for Healthcare Research and Quality. The Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the US Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Boston, MA.