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Comparative Study
. 2008 Jun 24;5(6):e131.
doi: 10.1371/journal.pmed.0050131.

Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure

Hans Bisgaard  1 , 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
Affiliations
Comparative Study

Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure

Hans Bisgaard et al. PLoS Med. .

Abstract

Background: Loss-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 findings: We 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.

Conclusions: We 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.

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Conflict of interest statement

Competing Interests: HB has been a consultant to, paid lecturer for, and holds sponsored grants from AstraZeneca, GSK, Merck, MedImmune, NeoLab, and Pfizer. He does not hold stock or options in any pharmaceutical company in the respiratory field. IM has filed two patents relating to genetic testing and therapy development aimed at the filaggrin gene. AC receives grant and research support from GlaxoSmithKline and is a consultant for GlaxoSmithKline and UCB Pharma, ALK; and at the speaker's bureau of Astra-Zeneca, GlaxoSmithKline, and UCB Pharma, ALK.

Figures

Figure 1
Figure 1. Kaplan-Meier Estimates of Cumulative Risk of Eczema in the COPSAC Cohort with and without FLG Mutation
Numbers at risk at are given below the graph. Dashed line, no mutation; solid line, mutation.
Figure 2
Figure 2. Kaplan-Meier Estimates of Cumulative Risk of Eczema in the MAAS Cohort with and without FLG Mutation
Numbers at risk at are given below the graph. Dashed line, no mutation; solid line, mutation.
Figure 3
Figure 3. COPSAC: Kaplan-Meier Estimates of Cumulative Risk of Eczema during the First Year of Life Stratified on Mutation and Cat at Birth Status
Numbers at risk at birth, 6, and 12 mo are given below the graph. Dashed line, no cat at birth; solid line, cat at birth.
Figure 4
Figure 4. MAAS: Kaplan-Meier Estimates of Cumulative Risk of Eczema during the First Year of Life Stratified on Mutation and Cat at Birth Status
Numbers at risk at birth, 6, and 12 mo are given below the graph. Dashed line, no cat at birth; solid line, cat at birth.
See this image and copyright information in PMC

References

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