Effects of Glutathione-S-Transferase M1, T1, and P1 on Childhood Lung Function Growth

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Abstract
The effects of glutathione-S-transferase (GST) M1, GSTT1 ,a nd all mortality emphasize the importance of attaining maximum GSTP1 genotypes on lung function growth were investigated in lung function (6, 7). 1,940 children enrolled in the Children's Health Study as fourth A broad spectrum of determinants for childhood lung graders (aged 8-11 years) in two cohorts during 1993 and 1996 function growth has been identified (1, 2, 8-11). Experiences and were followed annually over a 4-year period. Genotypes for during the in utero period affect lung function growth, as GSTM1 and GSTT1 and GSTP1 codon 105 variants (ile105 and val105) indicated by associations of adult lung function level with were determined using DNA from buccal cell specimens. We used exposure to maternal smoking, gestational age, and birth two-level regression models to estimate the effects of GSTM1, weight (8, 12-15). Early childhood respiratory infections, GSTT1, and GSTP1 genotypes on the adjusted annual average lung asthma, and airway hyper-responsiveness as well as childhood function growth. GSTM1 null was associated with deficits in annual exposures to air pollution and tobacco smoke are also associ- growth rates for FVC (0.21%; 95% confidence interval (CI),0.40, ated with reduced lung function growth, lower adult lung 0.03) and FEV1 (0.27%; 95% CI, 0.50, 0.04). Children who function, and increased risk for COPD. Familial aggregation were homozygous for the GSTP1 val105 allele had slower lung func- of FEV 1 and associations of COPD with candidate genes tion growth (FVC0.35%; 95% CI,0.62,0.07; and FEV10.34%; such as glutathione-S-transferase (GST) P1, epoxide hy- 95% CI, 0.68, 0.00) than children with one or more ile105 alleles. drolase, and 1-antitrypsin gene indicate that a genetic varia- Children with asthma who were homozygous for the GSTP1 val105 tion is likely to affect childhood lung growth; however, ge- allele had substantially larger deficits in FVC, FEV1, and maximal netic determinants of childhood lung function growth have mid-expiratory flow than children without asthma. The deficits in not been extensively studied (16-22). Understanding the con- FVC and FEV1 growth associated with both GSTM1 null and the GSTP1 tribution of common genetic variants to the complex pheno- val105 allele were largest and were statistically significant in non- type of lung function growth may clarify the pathophysiologic Hispanic white children. We conclude that GSTM1 and GSTP1 geno- pathways that are important for normal lung development types are associated with lung function growth in school children.