What is the evidence for interactions between filaggrin null mutations and environmental exposures in the aetiology of atopic dermatitis? A systematic review

Background: Epidemiological studies indicate that gene-environment interactions play a role in atopic dermatitis.

Objective: To review the evidence for gene-environment interactions in atopic dermatitis aetiology, focusing on FLG loss-of-function mutations.

Methods: Systematic search from inception to September 2018 in EMBASE, MEDLINE and BIOSIS. Search terms included all synonyms for atopic dermatitis (AD) and filaggrin/FLG; any genetic or epidemiological study design using any statistical methods were included. Quality assessment using criteria modified from guidance - ROBINS-I and Human Genome Epidemiology Network (HuGENET)- for non-randomised and genetic studies was completed, including consideration of power. Heterogeneity of study design and analyses precluded the use of meta-analysis.

Results: Of 1,817 papers identified, 12 fulfilled the inclusion criteria required and performed formal interaction testing. There was some evidence for FLG-environment interactions in six of the studies (P value for interaction ≤0.05) including early-life cat ownership, older siblings, water hardness, phthalate exposure, higher urinary phthalate metabolite levels (which all increased AD risk additional to FLG null genotype) and prolonged breastfeeding (which decreased AD risk in the context of FLG null genotype). Major limitations of published studies were low numbers of individuals with AD and FLG loss-of-function mutations and exposure to specific environmental factors (n=5 to 94), and variation in exposure definitions.

Conclusions and Relevance: Evidence on FLG-environment interactions in atopic dermatitis aetiology is limited. However, many of the studies lacked large enough sample sizes to fully assess these interactions. Further research is needed with larger sample sizes and clearly defined exposure assessment.