Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma.
BACKGROUND
Prenatal and infant acetaminophen exposure has been associated with an increased risk of childhood asthma phenotypes. Demonstration of biologically plausible interactions between these exposures and maternal and child antioxidant gene polymorphisms would strengthen causal inference.


OBJECTIVE
To explore potential interactions between prenatal and infant acetaminophen exposure and antioxidant genotypes on childhood asthma.


METHODS
In the Avon Longitudinal Study of Parents and Children, we typed a functional nuclear erythroid 2 p45-related factor 2 (Nrf2) polymorphism and glutathione S-transferase (GST) M1, T1, and P1 polymorphisms. Effects of prenatal and infant acetaminophen exposure on asthma phenotypes at 7 years were stratified by genotype in >4000 mothers and >5000 children.


RESULTS
Risk of asthma and wheezing associated with early gestation acetaminophen exposure was increased when maternal copies of the minor T allele of Nrf2 were present (P interactions, .02 and .04, respectively). Risk of asthma associated with late gestation exposure was higher when maternal GSTT1 genotype was present rather than absent (P interaction, .006), and risk of wheezing was increased when maternal GSTM1 was present (P interaction, .04). Although acetaminophen use in infancy was associated with an increased risk of atopy, child antioxidant genotype did not modify associations between infant acetaminophen use and asthma phenotypes. However, the increased risk of asthma and wheezing associated with late gestation acetaminophen exposure in the presence of maternal GSTM1 was further enhanced when GSTM1 was also present in the child.


CONCLUSIONS
Maternal antioxidant gene polymorphisms may modify the relation between prenatal acetaminophen exposure and childhood asthma, strengthening evidence for a causal association. In contrast, relations between infant acetaminophen use and asthma and atopy were not modified by child genotype and may be confounded by pre-existing wheeze or allergy.
Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College London, London, United Kingdom. s.shaheen@qmul.ac.uk
Seif O
SO
Shaheen
Roger B
RB
Newson
Susan M
SM
Ring
Matthew J
MJ
Rose-Zerilli
John W
JW
Holloway
A John
AJ
Henderson
D000082:Acetaminophen / Q000009:adverse effects*; D001249:Asthma / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D012307:Risk Factors
D051267:NF-E2-Related Factor 2; D000082:Acetaminophen; D005982:Glutathione Transferase