Variation in the GST mu locus and tobacco smoke exposure as determinants of childhood lung function.
BACKGROUND
The glutathione S-transferases (GSTs) are important detoxification enzymes.


OBJECTIVE
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.


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 FEV(1) 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.
Breton
Carrie V
CV
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, 90033 USA.
Vora
Hita
H
Salam
Muhammad T
MT
Islam
Talat
T
Wenten
Made
M
Gauderman
W James
WJ
Van den Berg
David
D
Berhane
Kiros
K
Peters
John M
JM
Gilliland
Frank D
FD
D000293:Adolescent; D002648:Child; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics; D011446:Prospective Studies; D012123:Pulmonary Ventilation / Q000235:genetics*; D012129:Respiratory Function Tests; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D014028:Tobacco Smoke Pollution; C483009:GSTM3 protein, human; C514654:GSTM4 protein, human; C524366:GSTM5 protein, human; D005982:Glutathione Transferase; C412602:glutathione S-transferase Mu 2