Novel childhood asthma genes interact with in utero and early-life tobacco smoke exposure.
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ABSTRACT:
SUBMITTER: Scholtens S
PROVIDER: S-EPMC3969577 | biostudies-literature | 2014 Mar
REPOSITORIES: biostudies-literature
Publications
Novel childhood asthma genes interact with in utero and early-life tobacco smoke exposure.
Scholtens Salome S Postma Dirkje S DS Moffatt Miriam F MF Panasevich Sviatlana S Granell Raquel R Henderson A John AJ Melén Erik E Nyberg Fredrik F Pershagen Göran G Jarvis Deborah D Ramasamy Adaikalavan A Wjst Matthias M Svanes Cecilie C Bouzigon Emmanuelle E Demenais Florence F Kauffmann Francine F Siroux Valérie V von Mutius Erika E Ege Markus Johannes MJ Braun-Fahrländer Charlotte C Genuneit Jon J Brunekreef Bert B Smit Henriette A HA Wijga Alet H AH Kerkhof Marjan M Curjuric Ivan I Imboden Medea M Thun Gian A GA Probst-Hensch Nicole N Freidin Maxim B MB Bragina Elena Iu EIu Deev I A IA Puzyrev V P VP Daley Denise D Park Julie J Becker Allan A Chan-Yeung Moira M Kozyrskyj Anita L AL Pare Peter P Marenholz Ingo I Lau Susanne S Keil Thomas T Lee Young-Ae YA Kabesch Michael M Wijmenga Cisca C Franke Lude L Nolte Ilja M IM Vonk Judith J Kumar Ashish A Farrall Martin M Cookson William O C M WO Strachan David P DP Koppelman Gerard H GH Boezen H Marike HM
The Journal of allergy and clinical immunology 20131206 3
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Project description:ObjectiveAssociations between single-nucleotide polymorphisms in the beta2-adrenergic receptor gene and asthma and wheeze have been inconsistent. Recent studies indicated that tobacco smoke affects beta2-adrenergic receptor gene expression and associations of beta2-adrenergic receptor gene variants with asthma in adults. We aimed to investigate the joint effects of in utero and childhood secondhand tobacco smoke exposure and 2 well-characterized functional single-nucleotide polymorphisms (Arg16Gly and Glu27Gln) of beta2-adrenergic receptor gene on asthma and wheezing in 3128 non-Hispanic and Hispanic white children of the Children's Health Study.MethodsWe fitted logistic regression models to estimate odds ratios and 95% confidence intervals for the independent and joint effects of these single-nucleotide polymorphisms and in utero and secondhand tobacco smoke exposure on asthma and wheeze outcomes.ResultsExposures to in utero maternal smoking and secondhand tobacco smoke were associated with wheezing. Children who were homozygous for the Arg16 allele and were exposed to maternal smoking in utero were at a threefold increased risk for lifetime wheeze compared with children who were unexposed and had at least 1 Gly16 allele. We found similar joint effects of secondhand tobacco smoke and Arg16Gly with wheezing. The risk for lifetime, current, and nocturnal wheeze increased with the number of smokers at home among Arg16 homozygous children. The results were consistent in 2 cohorts of children recruited in 1993 and 1996. Diplotype-based analyses were consistent with the single-nucleotide polymorphism-specific results. No associations were found for Glu27Gln.ConclusionsBoth in utero and childhood exposure to tobacco smoke were associated with an increased risk for wheeze in children, and the risks were greater for children with the Arg16Arg genotype or 2 copies of the Arg16-Gln27 diplotype. Exposures to smoking need to be taken into account when evaluating the effects of beta2-adrenergic receptor gene variants on respiratory health outcomes.
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Project description:BackgroundMaternal smoking during pregnancy is a risk factor for chronic disease later in life and has been associated with variability of DNA methylation at specific cytosine-phosphate-guanine (CpG) loci. We assessed the role of DNA methylation as a potential mediator of adverse effects of in utero tobacco smoke exposures on asthma outcomes in Latino children from the US mainland and Puerto Rico.MethodsRelationships between self-reported exposure and DNA methylation at CpG loci previously reported to be associated with maternal smoking were assessed in a subsample consisting of 572 children aged 8-21 years (310 cases with asthma, 262 healthy controls), sampled from a larger asthma case-control study. Subsequently, we assessed associations between top loci and asthma-related outcomes, followed by mediation analysis for loci for which associations with outcomes were observed.ResultsSelf-reported maternal smoking was associated with a -1.5% (95% confidence interval (CI) = -2.4%, -0.6%) lower methylation at CpG locus cg05575921 on the AHRR gene; a 1% increase in DNA methylation at the same locus resulted in an odds ratio (OR) of 0.90 (95% CI = 0.83, 0.96) for the odds of asthma. The OR for the indirect effect of maternal smoking on asthma mediated through methylation at the cg05575921 locus was 1.18 (95% CI = 1.07, 1.68), compared to the OR for the total effect of exposure in the parent study of 1.48 (95% CI = 1.03, 2.11).ConclusionsOur findings suggest potential mediation by DNA methylation in the association between maternal smoking during pregnancy and asthma status.
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Project description:BackgroundThe adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows.MethodsWe investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites.ResultsMaternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure.ConclusionIn this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis.
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Project description:BackgroundEpigenetic modifications, including DNA methylation, act as one potential mechanism underlying the detrimental effects associated with prenatal tobacco smoke (PTS) exposure. Methylation in a gene called AXL was previously reported to differ in response to PTS.MethodsWe investigated the association between PTS and epigenetic changes in AXL and how this was related to childhood asthma phenotypes. We tested the association between PTS and DNA methylation at multiple CpG loci of AXL at birth using Pyrosequencing in two separate study populations, the Children's Health Study (CHS, n = 799) and the Newborn Epigenetic Study (NEST, n = 592). Plasma cotinine concentration was used to validate findings with self-reported smoking status. The inter-relationships among AXL mRNA and miR-199a1 expression, PTS, and AXL methylation were examined. Lastly, we evaluated the joint effects of AXL methylation and PTS on the risk of asthma and related symptoms at age 10 years old.ResultsPTS was associated with higher methylation level in the AXL gene body in both CHS and NEST subjects. In the pooled analysis, exposed subjects had a 0.51% higher methylation level in this region compared to unexposed subjects (95% CI 0.29, 0.74; p < 0.0001). PTS was also associated with 21.2% lower expression of miR-199a1 (95% CI - 37.9, - 0.1; p = 0.05), a microRNA known to regulate AXL expression. Furthermore, the combination of higher AXL methylation and PTS exposure at birth increased the risk of recent episodes of bronchitic symptoms in childhood.ConclusionsPTS was associated with methylation level of AXL and the combination altered the risk of childhood bronchitic symptoms.
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Project description:PurposeCataract remains the primary cause of blindness in middle-income and low-income countries, with a known association with environmental factors including smoking. However, the relationship between early-life tobacco smoke exposures, including in utero tobacco smoke exposure and early initiation of smoking, and the risk of cataract incidence remains unclear. We aimed to examine the associations of early-life exposure to tobacco smoke with the risk of elderly-onset cataract.MethodsIn this prospective study, we included 330,528 participants aged 40 years or older who were recruited between 2006 and 2010. Early-life tobacco smoke exposures, including in utero, childhood, and adolescence exposure to tobacco smoke, as well as the type of tobacco smoke, were ascertained based on questionnaires at baseline. Elderly-onset cataract was ascertained using hospital inpatient records and cataract surgery records. Multivariable-adjusted Cox proportional hazards models were used to examine the association between early-life tobacco smoke exposures and incident cataract. Additionally, the association between different types of tobacco smoke and cataract risk was also explored.ResultsDuring a median follow-up of 12.04 years, 14,754 cases of incident cataract were documented. After adjusting confounders, the incidence of cataract significantly increased among participants with tobacco smoke exposures (hazard ratio [HR] = 1.13, 95% confidence interval [CI] = 1.09-1.18). Furthermore, individuals who were exposed to tobacco smoke in childhood (HR = 1.10, 95% CI = 1.03-1.21), adolescence (HR = 1.15, 95% CI = 1.10-1.21), and adulthood (HR = 1.12, 95% CI = 1.05-1.19) had an increased risk of cataract. Additionally, individuals who smoked cigars or pipes (HR = 1.26, 95% CI = 1.11-1.44), hand-rolled cigarettes (HR = 1.20, 95% CI = 1.05-1.36), and manufactured cigarettes (HR = 1.12, 95% CI = 1.08-1.17) were associated with an increased risk of cataract.ConclusionsIndividuals with early-life tobacco smoke exposures in childhood and adolescence significantly elevate the risks of cataract incidence in older age.Translational relevanceThis study identified cataract-associated risks and suggested interventions like banning youth smoking to reduce future cataract incidence.
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Project description:ObjectiveTo determine whether prenatal and childhood tobacco smoke exposure (TSE) are each independently associated with mild sleep-disordered breathing (SDB) symptoms throughout early childhood, and whether the association between childhood TSE and SDB differs according to the level of prenatal exposure.MethodsLongitudinal cohort study, using data from the Avon Longitudinal Study of Parents and Children, a population-based birth cohort from the United Kingdom. Primary exposures were repeated measures of mother-reported prenatal and childhood TSE through age 7 years. Outcomes were mother-reported measures of mild SDB symptoms, including snoring, mouth breathing, and witnessed apnea, repeated annually through age 7 years.ResultsA total of 12,030 children were followed for a median duration of 7 years. About 24.2% were exposed to prenatal tobacco smoke, 46.2% were exposed at least once in childhood, and 20.6% were exposed during both periods. Both prenatal and childhood TSE were associated with SDB symptoms throughout early childhood (adjusted OR [aOR] for any prenatal TSE 1.23; 95% confidence interval [CI] 1.08, 1.40; aOR for any childhood TSE 1.17; 95% CI 1.06, 1.29). We observed a dose-response effect between TSE and SBD symptoms, and found evidence of effect modification for those exposed during both time periods (combined high level exposure both prenatally and during childhood: aOR snoring 2.43 [95% CI 1.50, 3.93], aOR apnea 2.65 [95% CI 1.46, 4.82]).ConclusionsPrenatal and childhood TSE were both independently associated with mild SDB symptoms throughout early childhood in a dose-dependent manner, further supporting the critical importance of maintaining a tobacco-free environment throughout gestation and childhood.
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Project description:BackgroundOvarian cancer risk in adulthood may be affected by early life exposure to tobacco smoke. We investigated this relationship in two large prospective cohorts, the Nurses' Health Study (NHS) and NHSII.MethodsIn total, analyses included 110 305 NHS participants (1976-2016) and 112 859 NHSII participants (1989-2017). Self-reported early life smoking exposures were queried at baseline or follow-up questionnaires. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of ovarian cancer overall and by tumour histotype.ResultsOverall, ovarian cancer risk was not different among participants whose mothers did versus did not smoke during pregnancy (HR = 1.05, 95% CI: 0.87-1.27); however, an increased risk was observed among women who themselves were never smokers (HR = 1.38, 95% CI: 1.05-1.81) but not among ever smokers (HR = 0.86, 95% CI: 0.66-1.14; Pheterogeneity = 0.02). Compared with women who never smoked, ovarian cancer risk was similar for women who started to smoke at age <18 (HR = 0.98, 95% CI: 0.86-1.11) or ≥18 (HR = 1.02, 95% CI: 0.93-1.12). These associations did not differ by histotype (Pheterogeneity ≥0.35). Parental smoking in the home during childhood/adolescence was related to a 15% increased risk of ovarian cancer in adulthood (HR = 1.15, 95% CI: 1.04-1.27) and this association was suggestively stronger among women with non-serous/low-grade serous tumours (HR = 1.28, 95% CI: 1.02-1.61) versus high-grade serous/poorly differentiated tumours (HR = 1.09, 95% CI: 0.93-1.28; Pheterogeneity = 0.25).ConclusionsExposure to parental tobacco smoke in the home, but not early initiation of smoking, was associated with a modest elevated risk of ovarian cancer. Further investigations are required to confirm these findings and elucidate underlying mechanisms.
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Project description:(1) Background: Variants of the interleukin-1 receptor antagonist (IL1RN) gene, encoding an anti-inflammatory cytokine, are associated with asthma. Asthma is a chronic inflammatory disease of the airway influenced by interactions between genetic variants and environmental factors. We discovered a gene-environment interaction (GEI) of IL1RN polymorphisms with childhood environmental tobacco smoke (ETS) exposure on asthma susceptibility in an urban adult population. (2) Methods: DNA samples from the NYU/Bellevue Asthma Registry were genotyped for tag SNPs in IL1RN in asthma cases and unrelated healthy controls. Logistic regressions were used to study the GEI between IL1RN variants and childhood ETS exposures on asthma and early onset asthma, respectively, adjusting for population admixture and other covariates. (3) Results: Whereas the rare genotypes of IL1RN SNPs (e.g., GG in SNP rs2234678) were associated with decreased risk for asthma among those without ETS exposure (odds ratio OR = 0.215, p = 0.021), they are associated with increased risk for early onset asthma among those with childhood ETS (OR = 4.467, p = 0.021). (4) Conclusions: We identified a GEI between polymorphisms of IL1RN and childhood ETS exposure in asthma. Analysis of GEI indicated that childhood ETS exposure disrupted the protective effect of some haplotypes/genotypes of IL1RN for asthma and turned them into high-risk polymorphisms for early onset asthma.
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Project description:Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy number of 8 genes frequently deleted in ALL (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) was assessed in 559 pretreatment tumor samples from the California Childhood Leukemia Study. Parent and child's passive tobacco exposure was assessed using interview-assisted questionnaires as well as DNA methylation in aryl-hydrocarbon receptor repressor (AHRR), a sentinel epigenetic biomarker of exposure to maternal smoking during pregnancy. Multivariable Poisson regressions were used to test the association between the smoking exposures and total number of deletions. Deletion burden varied by subtype, with a lower frequency in high-hyperdiploid and higher frequency in ETV6-RUNX1 fusion ALL. The total number of deletions per case was positively associated with tobacco smoke exposure, in particular for maternal ever-smoking (ratio of means, RM, 1.31; 95% CI, 1.08-1.59), maternal smoking during pregnancy (RM, 1.48; 95% CI, 1.12-1.94), and during breastfeeding (RM, 2.11; 95% CI, 1.48-3.02). The magnitude of association with maternal ever-smoking was stronger in male children compared with females (Pinteraction = 0.04). The total number of deletions was also associated with DNA methylation at the AHRR epigenetic biomarker (RM, 1.32; 95% CI, 1.02-1.69). Our results suggest that prenatal and early-life tobacco smoke exposure increase the frequency of somatic deletions in children who develop ALL. Cancer Res; 77(7); 1674-83. ©2017 AACR.
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Project description:Animal studies have shown that in utero exposure to chemicals in tobacco smoke reduces female fertility, but epidemiological findings have been inconsistent.We examined the association between in utero exposure to tobacco smoke and female fertility among women in the Norwegian Mother and Child Cohort Study, enrolled from 1999 to 2007. Around the 17th week of pregnancy, participants reported how long they took to conceive (time to pregnancy), and whether their mother smoked while pregnant with the participant. This analysis included 48 319 planned pregnancies among women aged 15-44 years. We estimated fecundability odds ratios (FORs) using a discrete-time survival analysis, adjusting for age, education and adult tobacco smoking.The adjusted FOR for in utero exposure to tobacco smoke among all subjects was 0.96 [95% confidence interval (CI): 0.93, 0.98], among subjects reporting no adult tobacco smoking or passive exposure it was 0.96 (95% CI: 0.93, 0.99) and among subjects reporting adult tobacco smoking or passive exposure it was 0.95 (95% CI: 0.91, 0.99). We performed a probabilistic sensitivity analysis to estimate the effect of exposure and outcome misclassification on the results, and, as expected, the association became more pronounced after taking misclassification into account.This large cohort study supports a small-to-modest association between in utero exposure to tobacco smoke and reduced fertility.
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