Skin barrier‐related genes in childhood atopic dermatitis, asthma, and allergy: A systematic review and meta‐analysis

Atopic dermatitis (AD), asthma, food allergy, and respiratory allergy are common childhood conditions with significant disease burden. Current understanding implicates the skin-barrier and the dual-allergen hypotheses in the pathophysiology of these allergic conditions. This systematic review and meta-analysis aimed to investigate the role of genes associated with primary skin barrier dysfunction in childhood atopic conditions. We conducted a comprehensive search across Embase, MEDLINE, Emcare, CINAHL, and Cochrane Central databases, yielding 6018 abstracts and 941 full-text articles, of which 60 met the inclusion criteria. Quality assessment was performed using the Q-GENIE tool. The full protocol is available on the PROSPERO database (registration ID CRD42022355771). Our analysis confirms a role for the filaggrin (FLG) gene, with meta-analysis revealing associations between FLG loss-of-function (LOF) mutations and AD (OR 2.426, 95% CI 1.890-3.114) in cohort studies and (OR 4.44, 95% CI 2.42-8.12) in case-control studies, asthma (OR 1.90, 95% CI 1.33-2.71), and food allergy (OR 1.79, 95% CI 1.11-2.88) in cohort studies. No statistically significant associations were found between FLG mutations and food allergy in case-control studies, or respiratory allergies. Included studies with insufficient clinical homogeneity for meta-analysis were presented as narrative synthesis, with studies looking at genetic associations with FLG (n = 28), FLG-2 (n = 1) and IL-18 (n = 1). The findings underscore the critical role of FLG mutations in childhood allergic conditions, particularly AD and asthma. However, we did not identify quantitative evidence for a clinically significant role for other skin barrier-related genes in relation to childhood allergy. Limitations include the exclusion of non-English-language studies and potential omissions of genes not represented in the Gene Ontology Skin Barrier database. Future research could explore personalized medicine according to FLG genotype to mitigate the effects of environmental exposures and reduce the burden of atopic diseases in children.