Genetic variation in antioxidant enzymes and lung function.

Not all cigarette smokers develop chronic obstructive pulmonary disease, and discovering susceptibility factors is an important research priority. The oxidative burden of smoking may overwhelm antioxidant defenses, and vulnerabilities may exist as a result of sequence variants in genes encoding antioxidant enzymes. This study explored the association between genetic variation in a network of antioxidant enzymes and lung phenotypes. Linear models evaluated single-locus marker associations in 2387 European American and African American participants in the Health, Aging, and Body Composition Study. After corrections were made for multiple comparisons, 15 statistically significant associations were identified, all of which were for SNP by smoking interactions. The most statistically significant findings were for genes encoding members of the isocitrate dehydrogenase gene family (IDH3A, IDH3B, IDH2). For rs6107100 (IDH3B) the variant genotype was associated with a difference of 6% in the FEV(1)/FVC ratio in African American current smokers, but the SNP had little or no association with FEV(1)/FVC in former and never smokers (nominal p(interaction)=5×10(-6)). A variant of the peroxiredoxin gene (rs9787810, PRDX5) was associated with lower percentage predicted FEV(1) and a lower ratio in European American current smokers, with little or no association in other smoking groups (nominal p(interaction)=0.0001 and 0.0003, respectively). The studied genes have not been reported in previous candidate gene association studies, and thus the findings suggest novel mechanisms and targets for future research and provide evidence for a contribution of sequence variation in genes encoding antioxidant enzymes to susceptibility in smokers.