Leptin receptor gene polymorphisms and sex modify the association between acetaminophen use and asthma among young adults: results from two observational studies

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.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0892-y) contains supplementary material, which is available to authorized users.

Potential sex differences in human milk leptin and their association with asthma and wheeze phenotypes: Results of the Ulm Birth Cohorts

“…However, recognizing that other human milk components and maternal factors could influence human milk composition, human milk leptin should be investigated in combination with milk concentrations of leptin-binding protein. 6,39 Although sex plays a role in the natural history of asthma development, 24 there is limited, if any, evidence that leptin in human milk is secreted in concentrations specific for infant sex and it remains unclear how sexspecific responses to nutritional stimuli could contribute to asthma and wheeze development. Furthermore, effect estimates in SPATZ were directionally opposite when using leptin measured at 6 weeks and 6 months of lactation.…”

“…22,37,38 Additionally, leptin is apparently expressed differently between boys and girls, a phenomenon that may neither be solely explained by sex hormones nor the sex-dependent distribution of body fat. 13,14,39 Thus, physiologic sex-specific requirements of leptin may regulate human milk leptin concentrations. However, recognizing that other human milk components and maternal factors could influence human milk composition, human milk leptin should be investigated in combination with milk concentrations of leptin-binding protein.…”

“…Their expression levels have been shown to be associated with the development and severity of asthma 22,37,38 . Additionally, leptin is apparently expressed differently between boys and girls, a phenomenon that may neither be solely explained by sex hormones nor the sex‐dependent distribution of body fat 13,14,39 . Thus, physiologic sex‐specific requirements of leptin may regulate human milk leptin concentrations.…”

Immunologic, genetic, and ecological interplay of factors involved in allergic diseases

“…A similar study by Fuseini et al demonstrated the signal attenuation of house dust mite-induced type 2 and IL-17A inflammatory factors by the action of testosterone ( 41 ). Finally, the presence of sex-specific leptin and leptin receptor polymorphisms may also contribute to differences in asthma severity ( 42 ). Although the role of estrogen in allergic disease progression has been implicated, the results from such studies are inconclusive on whether the hormone leads to an ameliorative effect by inhibiting inflammasome activation or a pathologic effect by promoting type 2 proinflammatory cytokine production ( 43 , 44 ).…”

Recent advances in pharmacogenomics research of anti-asthmatic drugs: a narrative review

“…Arginases, which are encoded by ARG1 and ARG2, are metabolized in vivo into L-arginine, which in turn generates nitric oxide (NO) in the presence of nitric oxide synthase (NOS), and NO is an endogenous bronchodilator. Ziyab et al found that ARG1 polymorphisms (rs2781659 and rs2781667) were related to acute SABAinduced bronchodilation in asthmatic patients (16). A Dutch asthma population-based cohort study demonstrated that 2 polymorphisms in ARG2 (rs17249437 and rs3742879) were related to asthma and more serious airway obstruction (17).…”