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


OBJECTIVE
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 FEV(1), maximal mid-expiratory flow rate, and FVC and whether any of the genetic associations varied with levels of exposure to air pollutants.


RESULTS
We found that variation in the GSS locus was associated with differences in susceptibility of children for lung function growth deficits associated with NO(2), PM(10), PM(2.5), elemental carbon, organic carbon, and O(3). 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 FEV(1), 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 O(3), 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.
Breton
Carrie V
CV
Department of Preventive Medicine, USC Keck School of Medicine, 1540 Alcazar Street, CHP 236, Los Angeles, CA 90033, USA. breton@usc.edu
Salam
Muhammad T
MT
Vora
Hita
H
Gauderman
W James
WJ
Gilliland
Frank D
FD
D000397:Air Pollution / Q000009:adverse effects*; D002140:California; D002648:Child; D015331:Cohort Studies; D004781:Environmental Exposure; D005260:Female; D005500:Follow-Up Studies; D005540:Forced Expiratory Flow Rates / Q000235:genetics; D005541:Forced Expiratory Volume / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005978:Glutathione / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D008168:Lung / Q000254:growth & development / Q000503:physiopathology*; D008171:Lung Diseases / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D012129:Respiratory Function Tests / Q000379:methods
D005978:Glutathione
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