Microsomal epoxide hydrolase, glutathione S-transferase P1, traffic and childhood asthma.
BACKGROUND
Microsomal epoxide hydrolase (EPHX1) metabolises xenobiotics including polyaromatic hydrocarbons (PAHs). Functional variants at this locus have been associated with respiratory diseases. The effects of EPHX1 variants may depend upon exposures from tobacco smoke and traffic emissions that contain PAHs as well as variants in other enzymes in the PAH metabolic pathway such as glutathione S-transferase (GST) genes. A study was undertaken to investigate associations of variants in EPHX1, GSTM1, GSTP1 and GSTT1 with asthma and the relationships between asthma, EPHX1 metabolic phenotypes and exposure to sources of PAHs.


METHODS
Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate the associations of genetic variants and exposures with asthma phenotypes using data from 3124 children from the Children's Health Study.


RESULTS
High EPHX1 activity was associated with an increased risk for lifetime asthma (OR 1.51, 95% CI 1.14 to 1.98) which varied by GSTP1 Ile105Val genotype and by residential proximity to major roads (p for interaction = 0.006 and 0.03, respectively). Among children with GSTP1 105Val/Val genotype, those who had high EPHX1 phenotype had a fourfold (95% CI 1.97 to 8.16) increased risk of lifetime asthma than children with low/intermediate EPHX1 phenotype. Among children living within 75 metres of a major road, those with high EPHX1 activity had a 3.2-fold (95% CI 1.75 to 6.00) higher lifetime asthma risk than those with low/intermediate activity. The results were similar for current, early persistent and late onset asthma. Children with high EPHX1 phenotype, GSTP1 Val/Val genotype who lived <75 metres from a major road were at the highest asthma risk.


CONCLUSIONS
EPHX1 and GSTP1 variants contribute to the occurrence of childhood asthma and increase asthma susceptibility to exposures from major roads.
Salam
Muhammad T
MT
Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.
Lin
Pi-Chu
PC
Avol
Edward L
EL
Gauderman
W James
WJ
Gilliland
Frank D
FD
D000293:Adolescent; D001249:Asthma / Q000201:enzymology* / Q000235:genetics; D002648:Child; D016001:Confidence Intervals; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D011379:Prognosis
D051549:Glutathione S-Transferase pi; D004851:Epoxide Hydrolases
Eur J Epidemiol. 2005;20(9):775-82
16170661
Chest. 2005 Sep;128(3):1156-62
16162701
Thorax. 2005 Oct;60(10):814-21
16192366
Epidemiology. 2005 Nov;16(6):737-43
16222162
Chem Res Toxicol. 2006 Jan;19(1):68-78
16411658
Cell Tissue Res. 2006 Jun;324(3):423-32
16501997
Environ Health Perspect. 2006 May;114(5):766-72
16675435
J Allergy Clin Immunol. 2006 Nov;118(5):1097-104
17088135
Lancet. 2007 Feb 17;369(9561):571-7
17307103
Pediatr Allergy Immunol. 2005 Sep;16(6):539-41
16176403
Chem Res Toxicol. 2000 Mar;13(3):135-60
10725110
Eur J Pharmacol. 2000 Mar 30;393(1-3):265-77
10771023
Am J Respir Crit Care Med. 2000 May;161(5):1437-42
10806136
Am J Respir Crit Care Med. 2001 Feb;163(2):429-36
11179118
Respir Res. 2001;2(4):255-60
11686891
Am J Respir Crit Care Med. 2002 Aug 15;166(4):457-63
12186820
Hum Hered. 2003;55(1):27-36
12890923
Br J Cancer. 2003 Aug 18;89(4):702-6
12915882
Br J Clin Pharmacol. 2004 Feb;57(2):213-7
14748821
Environ Health Perspect. 2004 May;112(6):760-5
15121522
Eur Respir J. 2004 Jun;23(6):818-24
15218992
Hum Mutat. 2004 Sep;24(3):208-14
15300848
Chest. 2004 Oct;126(4):1071-8
15486366
Ann Hum Genet. 1987 May;51(Pt 2):95-106
3118757
Biochem J. 1994 May 15;300 ( Pt 1):271-6
8198545
Hum Mol Genet. 1994 Mar;3(3):421-8
7516776
N Engl J Med. 1995 Jan 19;332(3):133-8
7800004
Lancet. 1997 Aug 30;350(9078):630-3
9288046
Cancer Res. 1998 Dec 1;58(23):5291-3
9850050
Cancer Res. 1998 Dec 1;58(23):5340-3
9850062
Am J Respir Crit Care Med. 1999 Mar;159(3):760-7
10051248
Am J Respir Crit Care Med. 1999 Mar;159(3):768-75
10051249
Chem Biol Interact. 2004 Nov 20;150(2):149-59
15535985
Respirology. 2004 Nov;9(4):493-8
15612961
Pharmacol Rev. 2005 Mar;57(1):79-115
15734728