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Differential associations of allergic disease genetic variants with developmental profiles of eczema, wheeze and rhinitis.

ABSTRACT: BACKGROUND:Allergic diseases (eczema, wheeze and rhinitis) in children often present as heterogeneous phenotypes. Understanding genetic associations of specific patterns of symptoms might facilitate understanding of the underlying biological mechanisms. OBJECTIVE:To examine associations between allergic disease-related variants identified in a recent genome-wide association study and latent classes of allergic diseases (LCADs) in two population-based birth cohorts. METHODS:Eight previously defined LCADs between birth and 11 years: "No disease," "Atopic march," "Persistent eczema and wheeze," "Persistent eczema with later-onset rhinitis," "Persistent wheeze with later-onset rhinitis," "Transient wheeze," "Eczema only" and "Rhinitis only" were used as the study outcome. Weighted multinomial logistic regression was used to estimate associations between 135 SNPs (and a polygenic risk score, PRS) and LCADs among 6345 individuals from The Avon Longitudinal Study of Parents and Children (ALSPAC). Heterogeneity across LCADs was assessed before and after Bonferroni correction. Results were replicated in Manchester Asthma and Allergy Study (MAAS) (n = 896) and pooled in a meta-analysis. RESULTS:We found strong evidence for differential genetic associations across the LCADs; pooled PRS heterogeneity P-value = 3.3 × 10-14 , excluding "no disease" class. The associations between the PRS and LCADs in MAAS were remarkably similar to ALSPAC. Two SNPs (a protein-truncating variant in FLG and a SNP within an intron of GSDMB) had evidence for differential association (pooled P-values ? 0.006). The FLG locus was differentially associated across LCADs that included eczema, with stronger associations for LCADs with comorbid wheeze and rhinitis. The GSDMB locus in contrast was equally associated across LCADs that included wheeze. CONCLUSIONS AND CLINICAL RELEVANCE:We have shown complex, but distinct patterns of genetic associations with LCADs, suggesting that heterogeneous mechanisms underlie individual disease trajectories. Establishing the combination of allergic diseases with which each genetic variant is associated may inform therapeutic development and/or predictive modelling.

SUBMITTER: Clark H

PROVIDER: S-EPMC6899469 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Differential associations of allergic disease genetic variants with developmental profiles of eczema, wheeze and rhinitis.

Clark Hannah H Granell Raquel R Curtin John A JA Belgrave Danielle D Simpson Angela A Murray Clare C Henderson A John AJ Custovic Adnan A Paternoster Lavinia L

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 20191015 11

<h4>Background</h4>Allergic diseases (eczema, wheeze and rhinitis) in children often present as heterogeneous phenotypes. Understanding genetic associations of specific patterns of symptoms might facilitate understanding of the underlying biological mechanisms.<h4>Objective</h4>To examine associations between allergic disease-related variants identified in a recent genome-wide association study and latent classes of allergic diseases (LCADs) in two population-based birth cohorts.<h4>Methods</h4> ...[more]

PMID: 31441980

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Project description:The term "atopic march" has been used to imply a natural progression of a cascade of symptoms from eczema to asthma and rhinitis through childhood. We hypothesize that this expression does not adequately describe the natural history of eczema, wheeze, and rhinitis during childhood. We propose that this paradigm arose from cross-sectional analyses of longitudinal studies, and may reflect a population pattern that may not predominate at the individual level.Data from 9,801 children in two population-based birth cohorts were used to determine individual profiles of eczema, wheeze, and rhinitis and whether the manifestations of these symptoms followed an atopic march pattern. Children were assessed at ages 1, 3, 5, 8, and 11 y. We used Bayesian machine learning methods to identify distinct latent classes based on individual profiles of eczema, wheeze, and rhinitis. This approach allowed us to identify groups of children with similar patterns of eczema, wheeze, and rhinitis over time. Using a latent disease profile model, the data were best described by eight latent classes: no disease (51.3%), atopic march (3.1%), persistent eczema and wheeze (2.7%), persistent eczema with later-onset rhinitis (4.7%), persistent wheeze with later-onset rhinitis (5.7%), transient wheeze (7.7%), eczema only (15.3%), and rhinitis only (9.6%). When latent variable modelling was carried out separately for the two cohorts, similar results were obtained. Highly concordant patterns of sensitisation were associated with different profiles of eczema, rhinitis, and wheeze. The main limitation of this study was the difference in wording of the questions used to ascertain the presence of eczema, wheeze, and rhinitis in the two cohorts.The developmental profiles of eczema, wheeze, and rhinitis are heterogeneous; only a small proportion of children (? 7% of those with symptoms) follow trajectory profiles resembling the atopic march. Please see later in the article for the Editors' Summary.

Project description:Rationale: The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear. Objectives: To investigate within-individual patterns of morbidity of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood. Methods: We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin [FLG] mutations and 17q21 variants), increase the risk of multimorbidity. Measurements and Main Results: Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema+wheeze+rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2- to 3-fold, rs7216389 risk variant by 1.4- to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity. Conclusions: Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities.

Project description:BackgroundThe prevalence of allergy-related diseases (ARDs), including rhinitis, allergic conjunctivitis and eczema, is on the increase globally. The causes of this increase are not well established.ObjectivesTo investigate the risk factors associated with ARDs among schoolchildren in Uganda.MethodsWe conducted a secondary data analysis of a large asthma case-control study involving 1700 schoolchildren, 5-17 years, in urban Uganda. ARDs were defined according to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Skin prick testing (SPT) was conducted using standard procedures and allergen-specific IgE (asIgE) using ImmunoCAP® . We employed inverse probability weighted analysis to generate estimated prevalence data and weighted odds ratios.ResultsThe lifetime estimated weighted prevalence of reported rhinitis, allergic conjunctivitis and eczema was 43.3%, 39.5% and 13.5%; weighted prevalence in 12 months was 10.1%, 9.1% and 2.3%, respectively. There was overlap of ARDs, with 66.3% of 1193 schoolchildren who reported having ever an ARDs (including asthma) reporting two or more. Risk factors associated with reported rhinitis in the last 12 months were city residence at birth [adjusted odds ratio (95% confidence interval) 2.66 (1.42-4.99) compared to rural]; father's [2.62 (1.79-3.83)] and mother's history of allergic disease [2.12 (1.48-3.02)]; frequent de-worming in the last 12 months [2.01 (1.30-3.11), ≥2 versus none]; current high frequency of 'trucks passing on the street near home' [2.59 (1.48-4.52), 'almost all the time' versus rarely] and positive SPT [1.54 (1.09-2.18)] but not asIgE [1.38 (0.60-3.15)]. The same pattern of risk factors was observed for allergic conjunctivitis and eczema.ConclusionWe found extensive multi-morbidity of, and overlap in the risk factors for, rhinitis, conjunctivitis and eczema-similar to asthma risk factors-among schoolchildren in urban Uganda. This suggests a similar underlying cause for all ARDs, associated with exposure to urban lifestyles and environment in Uganda.

Project description:The occurrence of allergic multimorbidity (coexistence of asthma, allergic rhinitis and eczema) has not been evaluated longitudinally from early childhood up to adulthood in a population-based study sample. We aimed to determine the prevalence of allergic multimorbidity up to age 20 stratified by parental allergies and sex/gender using extensive prospective follow-up data from two decades of a birth cohort study.In 1990, we recruited 1314 healthy newborns from 6 maternity wards across Germany for the population-based MAS birth cohort study. The sample was purposely risk-enriched by increasing the proportion of children at high allergy risk (i.e. at least 2 allergic family members among parents and siblings) from 19% in the source population to 38% in the final sample. The remaining 62% of all MAS children had a low or no allergy risk. Symptoms, medication and doctor's diagnoses of allergic diseases have been assessed using standardized questionnaires including validated ISAAC questions in 19 follow-up assessments up to age 20. Allergic multimorbidity at each time point was defined as the coexistence of at least 2 of the following diseases in one participant: asthma, allergic rhinitis and eczema.Response at age 20 was 72% (n = 942) of all recruited participants. At age 20, 18.5% (95% CI, 15.0-22.5%) of all participants with allergic parents had 2 or 3 concurrent allergies as compared to only 6.3% (95% CI, 4.3-9.0%) of those with non-allergic parents. At this age, allergic multimorbidity was similar in women and men (12.7% (95% CI, 9.7-16.2%) vs. 11.6% (95% CI, 8.9-14.8%)), whereas single allergic diseases were slightly more common in women than men (24.2% (95% CI, 20.2-28.5%) vs. 20.1% (95% CI, 16.6-24.0%)). Asthma occurred more frequently with coexisting allergic rhinitis and/or eczema than as a single entity from pre-puberty to adulthood.Having parents with allergies is not only a strong predictor to develop any allergy, but it strongly increases the risk of developing allergic multimorbidity. In males and females alike, coexisting allergies were increasingly common throughout adolescence up to adulthood. Particularly asthma occurred in both sexes more frequently with coexisting allergies than as a single entity.

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Differential associations of allergic disease genetic variants with developmental profiles of eczema, wheeze and rhinitis.

Publications

Differential associations of allergic disease genetic variants with developmental profiles of eczema, wheeze and rhinitis.

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