Genetic variation in the glutathione synthesis pathway, air pollution, and children's lung function growth

Rationale: Glutathione plays an important role in antioxidant and inflammatory processes in the lung. Alterations in glutathione metabolism are a central feature of several chronic lung diseases. Objectives: To determine whether sequence variation in genes in the glutathione synthesis pathway alters susceptibility to air pollution effects on lung function. Methods: In this prospective study, 14,821 lung function measurements were taken on 2,106 children from 12 Southern California cities. Tagging single-nucleotide polymorphisms in glutathione metabolism pathway genes GSS, GSR, GCLM, and GCLC were genotyped by GoldenGate assay (Illumina, San Diego, CA). Mixed regression models were used to determine whether particular haplotypes were associated with FEV1, maximal mid-expiratory flow rate, and FVC and whether any of the genetic associations varied with levels of exposure to air pollutants. Measurements and Main Results: We found that variation in the GSS locus was associated with differences in susceptibility of children for lung function growth deficits associated with NO₂, PM₁₀, PM_2.5, elemental carbon, organic carbon, and O₃. The negative effects of air pollutants were largely observed within participants who had a particular GSS haplotype. The effects ranged from -124.2 to -149.1 for FEV₁, from -92.9 to -126.7 for FVC, and from -193.9 to -277.9 for maximal mid-expiratory flow rate for all pollutants except O₃, which showed a larger decrease in lung function in children without this haplotype. Conclusions: Variation in GSS was associated with differences in susceptibility to adverse effects of pollutants on lung function growth.