Abstract
BackgroundEpidemiologic studies have demonstrated associations between acetaminophen use and asthma. This investigation sought to determine whether sex modifies the acetaminophen-asthma association and whether leptin (LEP) and leptin receptor (LEPR) gene polymorphisms modulate the sex-specific associations.MethodsData from the Isle of Wight birth cohort (IOW; n = 1456, aged 18 years) and Kuwait University Allergy (KUA; n = 1154, aged 18–26 years) studies were analyzed. Acetaminophen use and current asthma were self-reported. Genotype information for eighteen polymorphisms in LEP and LEPR genes were available in the IOW study. Associations between acetaminophen use and asthma were stratified by sex and genotype. Poisson regression models with robust variance estimation were evaluated to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI).ResultsAcetaminophen use was dose-dependently associated with an increased prevalence of current asthma in the IOW and KUA studies. In both studies, sex-stratified analysis showed that acetaminophen use was associated with asthma among males, but not in females (Pinteraction < 0.05). Moreover, a sex- and genotype-stratified analysis of the IOW data indicated that acetaminophen was associated with asthma to a similar extent among males and females carrying two common alleles of LEPR polymorphisms. In contrast, among those carrying at least one copy of the minor allele of LEPR polymorphisms, the magnitude of association between acetaminophen use and asthma was pronounced among males (aPR = 6.83, 95% CI: 2.87–16.24), but not among females (aPR = 1.22, 95% CI: 0.61–2.45).ConclusionsThe identified sex-related effect modification of the acetaminophen-asthma association varied across LEPR genotypes, indicating that the sex-specific association was confined to individuals with certain genetic susceptibility. If the acetaminophen-asthma association is causal, then our findings will aid susceptibility-based stratification of at-risk individuals and augment preventive public health efforts.
Highlights
Epidemiologic studies have demonstrated associations between acetaminophen use and asthma
LEP/leptin receptor (LEPR) single nucleotide polymorphisms (SNPs), sex, and acetaminophen use in relation to asthma In analysis of the Isle of Wight (IOW) cohort, we explored whether the identified sex-related effect modification of the acetaminophen-asthma association varied across LEP and LEPR genotypes
In support of our hypothesis, we have demonstrated that acetaminophen use was associated with increased prevalence of current asthma and wheeze among male participants in both the IOW and Kuwait University Allergy (KUA) studies, but not in female participants
Summary
Epidemiologic studies have demonstrated associations between acetaminophen use and asthma. Prenatal and infant exposures to acetaminophen are associated with asthma development in childhood independent of factors that are indicative for acetaminophen use (e.g., pain, fever, and respiratory tract infections/influenza) [13]. The causal inference is further strengthened by results of meta-analyses [14,15,16,17] and by the observation of effect modification, in which maternal antioxidant gene polymorphisms modified the association between maternal use of acetaminophen during pregnancy and child risk of asthma [18]. The epidemiologically-observed association between acetaminophen use and asthma is biologically plausible and explained by the ability of acetaminophen to deplete glutathione, a key airway antioxidant [19]. Glutathione depletion has been shown to induce oxidative stress and promote inflammatory responses in the lungs [20, 21]
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