title: Lower prevalence of common filaggrin mutations in a community sample of atopic eczema: is disease severity important?
abstract: BACKGROUND
  Recent studies have shown an association of loss-of-function mutations in the filaggrin gene (FLG) with ichthyosis vulgaris and atopic eczema (AE). Case selection may have distorted the hitherto reported prevalence of FLG mutations and their relation to atopic disease. The aim of the study was to determine the true population prevalence of FLG mutations in unselected children with and without reported physician diagnoses of asthma, allergic rhinitis and AE and their relationship with family history of atopic disease.
  
  
  METHODS
  We used a nested case-control design by sampling children with reported doctor's diagnoses of AE, asthma and allergic rhinitis and randomly selected controls from a larger cross-sectional study (n = 1263). Most common FLG mutations R501X, 2282del4, and R2447X were screened in DNA extracted from defrosted urine samples. The relationship of the combined FLG variants with atopic diseases and with reported family history of AE, asthma, and rhinitis was assessed.
  
  
  RESULTS
  In the patient group one homozygote (R501X/R501X), 4 compound heterozygotes (3 R501X/2282del4, one 2282del4/R2447X), and 17 heterozygotes (10 R501X/wt, 5 2282del4/wt, and 2 R2447X/wt), in the control group 9 heterozygotes (5 R501X/wt, 4 2282del4/wt) were detected. The combined prevalence of FLG loss-of-function alleles was 5% in the control group and 9% in the atopic sample. In a subgroup analysis, the combination of allergic rhinitis and AE showed a significant relationship with FLG mutations, OR = 3.7 (1.01-12.67, p = 0.024). Likewise, significant relations with reported family history of asthma, OR = 4.35 (1.78-10.62, p = 0.0012), allergic rhinitis, OR = 2.33 (1.49-3.63, p = 0.0002), and AE, OR = 5.08 (2.78-9.30, p ≤ 0.0001) were observed. In contrast to clinical studies with higher percentages of severely affected persons, FLG mutations here showed a moderate association with atopic disease.
  
  
  CONCLUSIONS
  Case selection may be responsible for overestimating the prevalence of FLG mutations in atopic disease.
authors.affiliation: Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria. r.gruber@i-med.ac.at
authors.forename: Robert
authors.initials: R
authors.lastname: Gruber
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Daniela
authors.initials: D
authors.lastname: Grabher
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Horak
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
authors.forename: Peter
authors.initials: P
authors.lastname: Lercher
mesh_terms: D001317:Austria / Q000453:epidemiology; D002648:Child; D003876:Dermatitis, Atopic / Q000145:classification / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease / Q000145:classification / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D012720:Severity of Illness Index
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins