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Variation in the GST mu Locus and Tobacco Smoke Exposure as Determinants of Childhood Lung Function

¹ Department of Preventive Medicine and ² Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, California

Correspondence and requests for reprints should be addressed to Frank Gilliland, M.D., Ph.D., Department of Preventive Medicine, USC Keck School of Medicine, 1540 Alcazar Street, CHP 236, Los Angeles, CA 90033. E-mail: gillilan{at}usc.edu

Rationale: The glutathione S-transferases (GSTs) are important detoxification enzymes.

Objectives: To investigate effects of variants in GST mu genes on lung function and assess their interactions with tobacco smoke exposure.

Methods: In this prospective study, 14,836 lung function measurements were collected from 2,108 children who participated in two Southern California cohorts. For each child, tagging single nucleotide polymorphisms in GSTM2, GSTM3, GSTM4, and GSTM5 loci were genotyped. Using principal components and haplotype analyses, the significance of each locus in relation to level and growth of FEV₁, maximum midexpiratory flow rate (MMEF), and FVC was evaluated. Interactions between loci and tobacco smoke on lung function were also investigated.

Measurements and Main Results: Variation in the GST mu family locus was associated with lower FEV₁ (P = 0.01) and MMEF (0.04). Two haplotypes of GSTM2 were associated with FEV₁ and MMEF, with effect estimates in opposite directions. One haplotype in GSTM3 showed a decrease in growth for MMEF (–164.9 ml/s) compared with individuals with other haplotypes. One haplotype in GSTM4 showed significantly decreased growth in FEV₁ (–51.3 ml), MMEF (–69.1 ml/s), and FVC (–44.4 ml), compared with all other haplotypes. These results were consistent across two independent cohorts. Variation in GSTM2 was particularly important for FVC and FEV₁ among children whose mothers smoked during pregnancy.

Conclusions: Genetic variation across the GST mu locus is associated with 8-year lung function growth. Children of mothers who smoked during pregnancy and had variation in GSTM2 had lower lung function growth.

Key Words: FEV₁ • in utero • glutathione S-transferase • tobacco smoke

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject GSTM1 plays an important role in lung function development. The role of variants in other GSTM genes in lung development has yet to be determined. What This Study Adds to the Field Haplotypes of GSTM2, GSTM3, and GSTM4 are associated with lung function growth during adolescence. The association between GSTM2 haplotypes and lung function is modified by in utero exposure to tobacco smoke.