title: Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure.
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.
  
  
  RESULTS
  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.
authors.affiliation: Copenhagen Prospective Studies on Asthma in Childhood, Danish Paediatric Asthma Centre, Copenhagen, University Hospital Gentofte, Copenhagen, Denmark. bisgaard@copsac.com
authors.forename: Hans
authors.initials: H
authors.lastname: Bisgaard
authors.forename: Angela
authors.initials: A
authors.lastname: Simpson
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Klaus
authors.initials: K
authors.lastname: Bønnelykke
authors.forename: Irwin
authors.initials: I
authors.lastname: McLean
authors.forename: Somnath
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Christian B
authors.initials: CB
authors.lastname: Pipper
authors.forename: Liselotte B
authors.initials: LB
authors.lastname: Halkjaer
authors.forename: Brian
authors.initials: B
authors.lastname: Lipworth
authors.forename: Jenny
authors.initials: J
authors.lastname: Hankinson
authors.forename: Ashley
authors.initials: A
authors.lastname: Woodcock
authors.forename: Adnan
authors.initials: A
authors.lastname: Custovic
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000818:Animals; D002415:Cats / Q000276:immunology*; D018389:Codon, Nonsense / Q000502:physiology; D015331:Cohort Studies; D003876:Dermatitis, Atopic / Q000235:genetics*; D004285:Dogs; D004777:Environment; D004781:Environmental Exposure; D000091344:Filaggrin Proteins; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007381:Intermediate Filament Proteins / Q000235:genetics* / Q000502:physiology; D036801:Parturition; D012307:Risk Factors
chemical_list: D018389:Codon, Nonsense; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins