Research Article: Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Loss-of-Function Mutations Enhanced by Neonatal Cat Exposure

Date Published: June 24, 2008

Publisher: Public Library of Science

Author(s): Hans Bisgaard, Angela Simpson, Colin N.A Palmer, Klaus Bønnelykke, Irwin Mclean, Somnath Mukhopadhyay, Christian B Pipper, Liselotte B Halkjaer, Brian Lipworth, Jenny Hankinson, Ashley Woodcock, Adnan Custovic, Matthias Wjst

Abstract: BackgroundLoss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema.Methods and FindingsWe used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen (n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27–4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79–32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24–1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13–3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35–10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16–2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation.ConclusionsWe have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in children with FLG loss-of-function variants, but not amongst those without. FLG-deficient individuals may need to avoid cats but not dogs in early life.

Partial Text: We recently discovered in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) that loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema [1]. This finding has since been replicated in other populations [2–4], and the population attributable risk for eczema estimated at 11% [2].

The effects from FLG mutations in both cohorts occurred early in life as demonstrated by the Kaplan Meier curves (Figures 1 and 2), with hazard ratios (HR) of 2.90 (1.80–4.68) and 2.06 (1.40–3.05) in the first year and 0.71 (0.22–2.27) and 1.01 (0.48–2.51) after age 1 y (COPSAC and MAAS, respectively). We therefore focused the analysis on the interaction between FLG status and environmental exposures during the first year of life. Exposure variables in both cohorts were independent of FLG mutations.