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Author Bisgaard, H.; Simpson, A.; Palmer, C.N.A.; Bonnelykke, K.; McLean, I.; Mukhopadhyay, S.; Pipper, C.B.; Halkjaer, L.B.; Lipworth, B.; Hankinson, J.; Woodcock, A.; Custovic, A. url  doi
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  Title Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure Type Journal Article
  Year (down) 2008 Publication PLoS Medicine Abbreviated Journal PLoS Med  
  Volume 5 Issue 6 Pages e131  
  Keywords Age Factors; Age of Onset; Animals; Cats/*immunology; Codon, Nonsense/physiology; Cohort Studies; Dermatitis, Atopic/*genetics; Dogs; Environment; *Environmental Exposure; Gene Expression Regulation; Genetic Predisposition to Disease; Genotype; Humans; Infant; Infant, Newborn; Intermediate Filament Proteins/*genetics/physiology; Parturition; Risk Factors  
  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.  
  Address Copenhagen Prospective Studies on Asthma in Childhood, Danish Paediatric Asthma Centre, Copenhagen, University Hospital Gentofte, Copenhagen, Denmark. bisgaard@copsac.com  
  Corporate Author Thesis  
  Impact Factor 14,429 First Author Bisgaard, H. Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Senior Author Custovic, A.  
  ISSN 1549-1277 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:18578563; PMCID:PMC2504043 Approved no  
  Call Number Serial 123  
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