Genetic variation in antioxidant enzymes and rate of decline in lung function

Abstract

The oxidant/antioxidant balance in the lung is hypothesized to play an important role in chronic obstructive pulmonary disease (COPD). Deficits in antioxidant defenses due to variation in genes encoding antioxidant enzymes may cause accelerated lung function decline and increase disease risk. This study explored the association between genetic variation in a network of antioxidant enzymes and rate of decline in lung function phenotypes, including forced expiratory volume in the first second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC). 287 SNPs in 56 genes (MAF ≥ 1%) were analyzed using mixed effects models in 1,487 European American participants in the Health, Aging, and Body Composition study. The 7 top hits (nominal p<0.02, range 0.007 to 0.017) for FEV1 were in 4 genes: mGST3, GSTA4, GPX1, and GPX2. The rs6904771 locus in GSTA4 was associated with a 12 ml/yr steeper rate of decline in FEV1 per T allele. Markers in two genes (GCLC, GSTO2) were associated (nominal p<0.02) with the ratio of FEV1/FVC. mGST3, GPX1, and GPX2 have not been previously identified in human studies of lung outcomes, but agree with prior animal studies, and all 6 genes have known functional relevance to lung outcomes. In summary, genetic variants in antioxidant enzymes are associated with rate of decline in lung function. These pathways should be further investigated for possible antioxidant approaches to prevent and/or treat COPD. The project was supported by RC1 AG035835, R01 HL74104, R01 HL071022, genotyping services were provided by the Johns Hopkins University under N01‐HV‐48195 from the NHLBI, and NIA contracts N01‐AG‐6‐2101, N01‐AG‐2103, and N01‐AG‐6‐2106.