Skin Barrier Genes in Childhood Atopy
Key Takeaways
- FLG loss-of-function variants were associated with childhood atopic dermatitis, asthma, and food allergy in cohort analyses.
- Respiratory allergy was not significantly associated with FLG, and the food-allergy case-control meta-analysis was also not statistically significant.
- Only FLG, FLG-2, and IL18 appeared in the included literature, with FLG-2 and IL18 each limited to one narrative-only study, and quantitative evidence beyond FLG was not identified.
In pooled results, FLG loss-of-function variants were associated with childhood atopic dermatitis in cohort studies, with an odds ratio of 2.426 (95% CI 1.890-3.114). Across outcomes, FLG showed the clearest quantitative associations, while evidence for other barrier-related genes was sparse and generally unsuitable for pooling. Overall, the synthesis pointed to a recurring FLG pattern across childhood atopic disease rather than a broader gene-level pattern.
Investigators searched Embase, MEDLINE, Emcare, CINAHL, and Cochrane Central, screening 6,018 records after de-duplication and more than 900 full texts before including eligible studies. The review covered children and adolescents aged 0 to 17 years with atopic dermatitis, asthma or wheeze, food allergy, and respiratory allergy. When designs and outcomes were comparable, cohort and case-control studies were analyzed separately, while studies without sufficient clinical homogeneity were summarized narratively. The protocol was registered in PROSPERO, reporting followed PRISMA, quality assessment used Q-GENIE, and the analysis centered on pooled FLG findings alongside narrative-only evidence.
In pooled analyses, FLG loss-of-function variants were associated with childhood atopic dermatitis in case-control studies, with an odds ratio of 4.44 (95% CI 2.42-8.12). Cohort analyses also linked FLG with asthma, with an odds ratio of 1.90 (95% CI 1.33-2.71), and food allergy, with an odds ratio of 1.79 (95% CI 1.11-2.88). Respiratory allergy was not significantly associated in cohort meta-analysis, with an odds ratio of 1.53 (95% CI 0.85-2.73), and food allergy case-control pooling was also nonsignificant at 2.05 (95% CI 0.99-4.26). Several analyses showed substantial heterogeneity, especially food allergy case-control studies, and the quantitative evidence remained concentrated on FLG rather than multiple barrier genes.
Only FLG, FLG-2, and IL18 appeared in included studies, and FLG-2 and IL18 each came from one narrative-only report rather than pooled analyses. In the full review, authors said they did not identify quantitative evidence for a clinically significant role of other skin-barrier-related genes. They also described substantial heterogeneity, small subgroup sizes, variable mutation panels, differing diagnostic criteria and severity tools, and too few studies for subgroup analyses. Additional limitations included possible omissions from restricting gene selection to the Gene Ontology Skin Barrier database, exclusion of non-English studies, and combining FLG polymorphisms with mutations. The authors described future work in terms of standardized definitions and methods, broader candidate-gene coverage beyond FLG, more diverse global cohorts, and individualized understanding of atopic disease.