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.

Longitudinal trajectories of severe wheeze exacerbations from infancy to school age and their association with early‐life risk factors and late asthma outcomes

“…Children in the early‐onset frequent exacerbations trajectory were more likely to have co‐morbid eczema in early life (but not later in childhood). This is consistent with our recent finding that across different developmental profiles of wheeze, eczema and rhinitis, filaggrin locus (a major genetic risk factor for early‐onset eczema) is differentially associated with eczema with co‐morbid wheeze and rhinitis . This trajectory appeared to be associated with early‐onset allergic sensitization.…”

“…This is consistent with our recent finding that across different developmental profiles of wheeze, eczema and rhinitis, filaggrin locus (a major genetic risk factor for early-onset eczema) is differentially associated with eczema with co-morbid wheeze and rhinitis. 38 This trajectory appeared to be associated with early-onset allergic sensitization. This is in concordance with an exacerbation cluster identified by the Trousseau Asthma Programme, which could suggest that similar risk factors may be contributing to early-life sensitization and wheeze exacerbations.…”

Current Developments of Clinical Sequencing and the Clinical Utility of Polygenic Risk Scores in Inflammatory Diseases

“…However, ancestry-related genetic effects do not independently explain disparities in disease prevalence and disease control between the demographic groups under investigation. Clark et al investigated the relationship between a PRS and distinct developmental profiles of eczema, wheeze, and rhinitis identified using Bayesian machine learning methods (48). The authors provide evidence for differential association of the PRS across the entirety of developmental profiles, suggesting heterogeneous mechanisms underlying individual disease trajectories.…”

Genomics of asthma, allergy and chronic rhinosinusitis: novel concepts and relevance in airway mucosa

“…PSMD3 (chromosome 17q21) is a multicatalytic proteinase complex for proteasome and are distributed in many cells and have been reported to associate to atopic march and to atopic eczema and wheeze [ 111 ].…”