title: Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth.
abstract: Copenhagen Prospective Study on Asthma in Childhood (COPSAC) was one of the discovery cohorts of the association between eczema and variants in the filaggrin coding gene (FLG). Here, we study the FLG-associated risk of asthma symptoms in early life and describe the temporal relationship in the development of the different FLG-associated atopic outcomes: asthma, sensitization and eczema, assessed longitudinally from birth. A high-risk cohort of 411 children was assessed in a prospective clinical study from birth to school-age. Asthma, acute severe asthma exacerbations, sensitization and eczema were diagnosed prospectively by the investigators. FLG variants R501X and Del4 were determined in 382 Caucasians. Filaggrin variants increased risk of developing recurrent wheeze, asthma and asthma exacerbations (hazard ratio 1.82 [1.06-3.12], p = 0.03), which was expressed within the first 1.5 yr of life. Children with filaggrin variants had a marked and persistent increase in acute severe asthma exacerbations from 1 yr of age (incidence ratio 2.40 [1.19-4.81], p = 0.01) and increased risk of asthma by age 5 (odds ratio 2.62 [1.12-6.11], p = 0.03). FLG variants increased the risk of eczema, manifesting fully in the first year of life (point prevalence ratio for age 0-5 was 1.75 [1.29-2.37]; p-value = 0.0003) contrasting the increased risk of specific sensitization by age 4 (odds ratio 3.52 [1.72-7.25], p = 0.0007) but not age 1.5. This study describes a FLG-associated pattern of atopic diseases characterized by the early onset of asthma symptoms and eczema and later development of sensitization. The association of filaggrin variants with asthma suggests skin barrier dysfunction as a novel, and potentially modifiable, mechanism driving early childhood asthma.
authors.affiliation: Copenhagen Studies on Asthma in Childhood, Copenhagen University Hospital, Gentofte, Copenhagen, Denmark. kb@copsac.dk
authors.forename: Klaus
authors.initials: K
authors.lastname: Bønnelykke
authors.forename: Christian B
authors.initials: CB
authors.lastname: Pipper
authors.forename: Roger
authors.initials: R
authors.lastname: Tavendale
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Hans
authors.initials: H
authors.lastname: Bisgaard
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D001249:Asthma / Q000097:blood / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D002675:Child, Preschool; D005260:Female; D000091344:Filaggrin Proteins; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D015994:Incidence; D007223:Infant; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic; D015995:Prevalence
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D007073:Immunoglobulin E