Recent observations that disease risk can be transmitted across generations without the need for direct exposure of the child to the index environmental insult has sparked interest in ...transgenerational inheritance. Epigenetics describes processes that modify gene expression without a change in the nucleotide sequence. Epigenetic processes can be induced in response to environmental exposures, can influence disease risk, and might explain these multigenerational effects. In experimental models a number of epigenetic mechanisms have been identified that could mediate vertical transmission of epigenetic inheritance. However, relevance of these findings to human disease is not yet clear. An alternative model is one in which transgenerational inheritance of disease risk requires the presence of exposure-related diseases in the mother during pregnancy (termed induced epigenetic transmission model). A number of cross-sectional studies have investigated multigenerational effects in allergy and asthma. However, given the early-life origins of asthma and allergy, birth cohort studies are ideal to investigate the effect of genetic predisposition, epigenetics, and environmental exposures, avoiding pitfalls, such as recall bias and confounding by ongoing exposures, disease, and treatment. The well-characterized 3 generations of the Isle of Wight cohort include 2 consecutive birth cohorts, providing longitudinal data that can be studied for epigenetic transfer of information, such as the effect of grand parental smoking or exposure to other toxic compounds. Further large multigenerational birth cohorts are needed to establish the clinical relevance of this phenomenon and differentiate between vertical and induced transmission models, which might influence future preventive strategies.
Background Filaggrin is an epidermal protein that has a role in skin barrier function. Filaggrin loss-of-function ( FLG -LOF) mutations are a significant risk factor for eczema and atopy, but their ...association with food allergy (FA) is less clear. Objective We explored the longitudinal relationship between 3 common FLG -LOF mutations and FA using the Isle of Wight birth cohort. Methods FA diagnosis was based on recognized allergic reactions within 4 hours after exposure to known food allergens. Food allergen sensitization (FAS) was identified by using skin prick tests conducted between 1 and 18 years of age to a range of food allergens. Three FLG mutations were genotyped in 1150 (79%) of 1456 children. The temporal relationships between FA, FAS, and eczema in children with FLG mutations were explored by using path analysis with total, direct, and indirect effect models. Results There was a significant total effect of FLG- LOF mutations on the risk of FA in later childhood at the ages of 10 (odds ratio, 31.46; 95% CI, 2.86 to >100) and 18 (odds ratio, 4.25; 95% CI, 1.55-11.61) years. Path analysis showed that there was no direct effect of FLG -LOF mutations on FA at any age; however, an indirect effect was found on FA at all ages through eczema and FAS in the earlier years. Conclusion FLG -LOF mutations are associated with FA in older children through eczema and FAS during early childhood. Our results highlight a biologically plausible pathway, which suggests that skin barrier function is important in the development and persistence of FA.
Genetics of allergic disease Holloway, John W., PhD; Yang, Ian A., MBBS, PhD; Holgate, Stephen T., MD, DSc, FMed Sci
Journal of allergy and clinical immunology,
02/2010, Letnik:
125, Številka:
2
Journal Article
Recenzirano
Allergic diseases are complex genetic diseases resulting from the effect of multiple genetic and interacting environmental factors on their pathophysiology. Recent years have seen considerable ...progress in unraveling the contribution of these factors to an individual subject's susceptibility to, subsequent development of, and severity of disease. This has resulted in increasing insight into novel areas of allergic disease pathophysiology, for example the significant role played by locally acting tissue susceptibility factors like epithelial/epidermal barrier function and remodeling, such as filaggrin, ADAM33 , and GSDML / ORMDL3 , in patients with atopic dermatitis and asthma. Furthermore, studies of gene-environment interactions and Mendelian randomization approaches have led to increased insight into the importance of environmental triggers for allergic disease. Studies of the timing of action of genetic variants in determining disease susceptibility have highlighted the importance of in utero development and early life in determining susceptibility to allergic disease. In the future, genetic discoveries in allergic disease will potentially lead to better endophenotyping, prognostication, prediction of treatment response, and insights into molecular pathways to develop more targeted therapy for these conditions.
Background The parent-of-origin effect is important in understanding the genetic basis of childhood allergic diseases and improving our ability to identify high-risk children. Objective We sought to ...investigate the parent-of-origin effect in childhood allergic diseases. Methods The Isle of Wight Birth Cohort (n = 1456) has been examined at 1, 2, 4, 10, and 18 years of age. Information on the prevalence of asthma, eczema, rhinitis, and environmental factors was obtained by using validated questionnaires. Skin prick tests were carried out at ages 4, 10, and 18 years, and total IgE measurement was carried out at 10 and 18 years. Parental history of allergic disease was assessed soon after the birth of the child, when maternal IgE levels were also measured. Prevalence ratios (PRs) and their 95% CIs were estimated, applying log-linear models adjusted for confounding variables. Results When stratified for sex of the child, maternal asthma was associated with asthma in girls (PR, 1.91; 95% CI, 1.34-2.72; P = .0003) but not in boys (PR, 1.29; 95% CI, 0.85-1.96; P = .23), whereas paternal asthma was associated with asthma in boys (PR, 1.99; 95% CI, 1.42-2.79; P < .0001) but not in girls (PR, 1.03; 95% CI, 0.59-1.80; P = .92). Maternal eczema increased the risk of eczema in girls (PR, 1.92; 95% CI, 1.37-2.68; P = .0001) only, whereas paternal eczema did the same for boys (PR, 2.07; 95% CI, 1.32-3.25; P = .002). Similar trends were observed when the effect of maternal and paternal allergic disease was assessed for childhood atopy and when maternal total IgE levels were related to total IgE levels in children at ages 10 and 18 years. Conclusions The current study indicates a sex-dependent association of parental allergic conditions with childhood allergies, with maternal allergy increasing the risk in girls and paternal allergy increasing the risk in boys. This has implications for childhood allergy prediction and prevention.
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. Conclusion 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.
Background Alcohol consumption in western pregnant women is not uncommon and could be a risk factor for childhood atopic disease. However, reported alcohol intake may be unreliable, and associations ...are likely to be confounded. Objective We aimed to study the relation between prenatal alcohol exposure and atopic phenotypes in a large population-based birth cohort with the use of a Mendelian randomization approach to minimize bias and confounding. Methods In white mothers and children in the Avon Longitudinal Study of Parents and Children (ALSPAC) we first analyzed associations between reported maternal alcohol consumption during pregnancy and atopic outcomes in the offspring measured at 7 years of age (asthma, wheezing, hay fever, eczema, atopy, and total IgE). We then analyzed the relation of maternal alcohol dehydrogenase (ADH)1B genotype (rs1229984) with these outcomes (the A allele is associated with faster metabolism and reduced alcohol consumption and, among drinkers, would be expected to reduce fetal exposure to ethanol). Results After controlling for confounders, reported maternal drinking in late pregnancy was negatively associated with childhood asthma and hay fever (adjusted odds ratio OR per category increase in intake: 0.91 95% CI, 0.82-1.01 and 0.87 95% CI, 0.78-0.98, respectively). However, maternal ADH1B genotype was not associated with asthma comparing carriers of A allele with persons homozygous for G allele (OR, 0.98 95% CI, 0.66-1.47) or hay fever (OR, 1.11 95% CI, 0.71-1.72), nor with any other atopic outcome. Conclusion We have found no evidence to suggest that prenatal alcohol exposure increases the risk of asthma or atopy in childhood.
Background Several studies have suggested that chromosome 19q13.1-3 contains asthma susceptibility genes. Objective Linkage and association analyses using 587 United Kingdom and Dutch asthma families ...(n = 2819 subjects) were used to investigate this region. Methods A 3-phase procedure was used: (1) linkage and association analyses using 15 microsatellite markers spanning 14.4 mega base pairs (Mbps) on 19q13, (2) fine mapping of the refined region using 26 haplotype tagging single nucleotide polymorphisms (SNPs), and (3) dense gene analyses using 18 SNPs evaluated for association with asthma, bronchial hyperresponsiveness (BHR), FEV1 , plasma urokinase plasminogen activator receptor (PLAUR), and rate of annual FEV1 decline in subjects with asthma. Results The microsatellite analyses provided tentative support for an asthma/lung function susceptibility locus (48.9-49.1Mbps), and fine mapping localized modest association to the PLAUR gene. PLAUR SNPs in the 5′ region, intron 3, and 3′ region are associated with asthma and BHR susceptibility and predict FEV1 and plasma PLAUR levels. SNPs in the 5′ region showed association for asthma (2 populations), FEV1 (2 populations), and BHR (2 populations) phenotypes. SNPs in intron 3 showed association with asthma (2 populations) and BHR (3 populations). Importantly, the same 5′ region and intron 3 SNPs were associated with plasma PLAUR levels. The same 5′ region and 3′ region SNPs were found to be determinants of FEV1 decline in subjects with asthma. Conclusion This study represents the first report to identify PLAUR as a potential asthma susceptibility gene and determine PLAUR regions underlying this association, including a role in influencing plasma PLAUR levels. Finally, the association of PLAUR with lung function decline supports a role for PLAUR in airway remodeling in asthma.
Glutathione peroxidase (GPX) 4 is a unique membrane-associated selenium-dependent antioxidant enzyme that can directly reduce phospholipid hydroperoxides and protect against oxidative stress in ...mammalian cells.3 Aside from its antioxidant role, GPX4 has been implicated in lipoxygenase metabolism,4 which has major relevance to leukotriene synthesis and inflammatory signaling in asthma. ...demonstration of an interaction between selenium status and GPX4 genotype on asthma risk could strengthen the evidence for a causal role of selenium. Villette et al4 proposed that the rs713041 SNP in the 3' untranslated region of GPX4 may influence how efficiently selenocysteine is incorporated into GPX4, leading to altered GPX4 synthesis in response to variations in selenium supply.4 There is other evidence confirming that T/C variation (rs713041) has functional consequences,7 including a study showing that in individuals with the GPX4 (rs713041) TT genotype, oxidative stress decreased as in vivo selenium concentrations Furthermore, in vitro, selenium is necessary for the maximum expression of GPX4 in human lung epithelial cells.9 We therefore propose that low maternal blood selenium concentration leads to suboptimal GPX4 activity and impaired antioxidant defenses against oxidative stress in fetal airway epithelium, leading to epithelial damage, which, in turn, contributes to the pathogenesis of asthma.
The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age ...group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype.
We did this multicentre, parallel-group, randomised, placebo-controlled trial between Oct 1, 2010, and Dec 20, 2013, at 21 primary care sites and 41 secondary care sites in England and Scotland. Children aged 10 months to 5 years with two or more wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) via a permuted block schedule (size ten), to receive intermittent montelukast or placebo given by parents at each wheeze episode over a 12 month period. Clinical investigators and parents were masked to treatment group and genotype strata. The primary outcome was number of unscheduled medical attendances for wheezing episodes. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01142505.
We randomly assigned 1358 children to receive montelukast (n=669) or placebo (n=677). Consent was withdrawn for 12 (1%) children. Primary outcome data were available for 1308 (96%) children. There was no difference in unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 SD 2·6 vs 2·3 2·7; incidence rate ratio IRR 0·88, 95% CI: 0·77–1·01; p=0·06). Compared with placebo, unscheduled medical attendances for wheezing episodes were reduced in children given montelukast in the 5/5 stratum (2·0 2·7 vs 2·4 3·0; IRR 0·80, 95% CI 0·68–0·95; p=0·01), but not in those in the 5/x+x/x stratum (2·0 2·5 vs 2·0 2·3; 1·03, 0·83–1·29; p=0·79, pinteraction=0·08). We recorded one serious adverse event, which was a skin reaction in a child allocated to placebo.
Our findings show no clear benefit of intermittent montelukast in young children with wheeze. However, the 5/5 ALOX5 promoter genotype might identify a montelukast-responsive subgroup.
Medical Research Council (UK) and National Institute for Health Research.
Background A disintegrin and metalloprotease 33 (ADAM33) polymorphism is strongly associated with asthma and bronchial hyperresponsiveness. Although considered to be a mesenchymal cell–specific gene, ...recent reports have suggested epithelial expression of ADAM33 in patients with severe asthma. Objectives Because dysregulated expression of ADAM33 can contribute to disease pathogenesis, we characterized the mechanism or mechanisms that control its transcription and investigated ADAM33 expression in bronchial biopsy specimens and brushings from healthy and asthmatic subjects. Methods The ADAM33 promoter and CpG island methylation were analyzed by using bioinformatics, luciferase reporters, and bisulfite sequencing of genomic DNA. Epithelial-mesenchymal transition was induced by using TGF-β1. ADAM33 mRNA was scrutinized in bronchial biopsy specimens and brushings by using reverse transcriptase–quantitative polymerase chain reaction, melt-curve analysis, and direct sequencing. Results The predicted ADAM33 promoter (−550 to +87) had promoter transcriptional activity. Bisulfite sequencing showed that the predicted promoter CpG island (−362 to +80) was hypermethylated in epithelial cells but hypomethylated in ADAM33-expressing fibroblasts. Treatment of epithelial cells with 5-aza-deoxycytidine caused demethylation of the CpG island and induced ADAM33 expression. In contrast, phenotypic transformation of epithelial cells through a TGF-β–induced epithelial-mesenchymal transition was insufficient to induce ADAM33 expression. ADAM33 mRNA was confirmed in bronchial biopsy specimens, but no validated signal was detected in bronchial brushings from healthy or asthmatic subjects. Conclusion The ADAM33 gene contains a regulatory CpG island within its promoter, the methylation status of which tightly controls its expression in a cell type–specific manner. ADAM33 repression is a stable feature of airway epithelial cells, irrespective of disease.
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