title: No association between loss-of-function mutations in filaggrin and diabetes, cardiovascular disease, and all-cause mortality.
abstract: BACKGROUND
  Common loss-of-function mutations in the filaggrin gene (FLG) are a major predisposing risk factor for atopic disease due to reduced epidermal filaggrin protein levels. We previously observed an association between these mutations and type 2 diabetes and hypothesized that an inherited impairment of skin barrier functions could facilitate low-grade inflammation and hence increase the risk of diabetes and cardiovascular disease. We examined the association between loss-of-function mutations in FLG and diabetes, stroke, ischemic heart disease (IHD), and all-cause mortality in the general population.
  
  
  METHODS
  The R501X and 2282del4 loss-of function mutations in FLG were genotyped in four Danish study populations including a total of 13373 adults aged 15-77 years. Two of the studies also genotyped the R2447X mutation. By linkage to Danish national central registers we obtained information for all participants on dates of diagnoses of diabetes, stroke, and IHD, as well as all-cause mortality. Data were analyzed by Cox proportional hazard models and combined by fixed effect meta-analyses.
  
  
  RESULTS
  In meta-analyses combining the results from the four individual studies, carriage of loss-of-function mutations in FLG was not associated with incident diabetes (hazard ratio (HR) (95% confidence intervals (CI)) = 0.95 (0.73, 1.23), stroke (HR (95% CI) = 1.27 (0.97, 1.65), ischemic heart disease (HR (95%CI) = 0.92 (0.71, 1.19), and all-cause mortality (HR (95%CI) = 1.02 (0.83, 1.25)). Similar results were obtained when including prevalent cases in logistic regression models.
  
  
  CONCLUSIONS
  Our results suggest that loss-of-function mutations in FLG are not associated with type 2 diabetes, cardiovascular disease, and all-cause mortality. However, larger studies with longer follow-up are needed to exclude any associations.
authors.affiliation: Research Centre for Prevention and Health, Copenhagen University Hospital Glostrup, Glostrup, Denmark.
authors.forename: Lise Lotte N
authors.initials: LL
authors.lastname: Husemoen
authors.affiliation: Research Centre for Prevention and Health, Copenhagen University Hospital Glostrup, Glostrup, Denmark.
authors.forename: Tea
authors.initials: T
authors.lastname: Skaaby
authors.affiliation: Research Centre for Prevention and Health, Copenhagen University Hospital Glostrup, Glostrup, Denmark ; Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.affiliation: National Allergy Research Centre, Department of Dermato Allergology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Thyssen
authors.affiliation: Department of Clinical Biochemistry, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Meldgaard
authors.affiliation: Department of Clinical Biochemistry, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: Pal B
authors.initials: PB
authors.lastname: Szecsi
authors.affiliation: Department of Clinical Biochemistry, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Stender
authors.affiliation: National Allergy Research Centre, Department of Dermato Allergology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
authors.forename: Jeanne Duus
authors.initials: JD
authors.lastname: Johansen
authors.affiliation: Research Centre for Prevention and Health, Copenhagen University Hospital Glostrup, Glostrup, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Linneberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003718:Denmark / Q000453:epidemiology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009154:Mutation; D017202:Myocardial Ischemia / Q000453:epidemiology / Q000235:genetics*; D020521:Stroke / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins