title: Filaggrin genotype determines functional and molecular alterations in skin of patients with atopic dermatitis and ichthyosis vulgaris.
abstract: BACKGROUND
  Several common genetic and environmental disease mechanisms are important for the pathophysiology behind atopic dermatitis (AD). Filaggrin (FLG) loss-of-function is of great significance for barrier impairment in AD and ichthyosis vulgaris (IV), which is commonly associated with AD. The molecular background is, however, complex and various clusters of genes are altered, including inflammatory and epidermal-differentiation genes.
  
  
  OBJECTIVE
  The objective was to study whether the functional and molecular alterations in AD and IV skin depend directly on FLG loss-of-function, and whether FLG genotype determines the type of downstream molecular pathway affected.
  
  
  RESULTS
  Patients with AD/IV (n = 43) and controls (n = 15) were recruited from two Swedish outpatient clinics and a Swedish AD family material with known FLG genotype. They were clinically examined and their medical history recorded using a standardized questionnaire. Blood samples and punch biopsies were taken and trans-epidermal water loss (TEWL) and skin pH was assessed with standard techniques. In addition to FLG genotyping, the STS gene was analyzed to exclude X-linked recessive ichthyosis (XLI). Microarrays and quantitative real-time PCR were used to compare differences in gene expression depending on FLG genotype. Several different signalling pathways were altered depending on FLG genotype in patients suffering from AD or AD/IV. Disease severity, TEWL and pH follow FLG deficiency in the skin; and the number of altered genes and pathways are correlated to FLG mRNA expression.
  
  
  CONCLUSIONS
  We emphasize further the role of FLG in skin-barrier integrity and the complex compensatory activation of signalling pathways. This involves inflammation, epidermal differentiation, lipid metabolism, cell signalling and adhesion in response to FLG-dependent skin-barrier dysfunction.
authors.affiliation: Dermatology Unit, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. marten.winge@ki.se
authors.forename: Mårten C G
authors.initials: MC
authors.lastname: Winge
authors.forename: Torborg
authors.initials: T
authors.lastname: Hoppe
authors.forename: Berit
authors.initials: B
authors.lastname: Berne
authors.forename: Anders
authors.initials: A
authors.lastname: Vahlquist
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: Maria
authors.initials: M
authors.lastname: Bradley
authors.forename: Hans
authors.initials: H
authors.lastname: Törmä
mesh_terms: D000328:Adult; D000368:Aged; D002448:Cell Adhesion; D002454:Cell Differentiation; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000473:pathology; D005260:Female; D000091344:Filaggrin Proteins; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016112:Ichthyosis Vulgaris / Q000235:genetics / Q000473:pathology; D007249:Inflammation; D007381:Intermediate Filament Proteins / Q000235:genetics*; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000473:pathology*; D011795:Surveys and Questionnaires
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D012333:RNA, Messenger