Contact Dermatitis • Original Article COD Contact Dermatitis Filaggrin mutations are strongly associated with contact sensitization in individuals with dermatitis Jacob P. Thyssen 1 , Allan Linneberg 2 , Katrine Ross-Hansen 1 , Berit C. Carlsen 1 , Michael Meldgaard 3 , Pal B. Szecsi 3 , Steen Stender 3 , Torkil Menn ´ e 1 and Jeanne D. Johansen 1 1 Department of Dermato-Allergology, National Allergy Research Centre, Copenhagen University Hospital Gentofte, 2900 Hellerup, Denmark, 2 Research Centre for Prevention and Health, Copenhagen University Hospital Glostrup, 2600 Glostrup, Denmark, and 3 Department of Clinical Biochemistry, Copenhagen University Hospital Gentofte, 2900 Hellerup, Denmark doi:10.1111/cod.12021 Summary Background. Although heterozygous filaggrin gene (FLG) mutation carriers seem to have an increased risk of atopic, irritant and allergic nickel dermatitis, it remains unclear whether the risk of contact sensitization to allergens other than nickel is also elevated in FLG mutation carriers. Objectives. We hypothesized that heterozygous FLG mutation carriers who suffer from dermatitis will have strongly reduced or even absent filaggrin levels during episodes of inflammation, potentially increasing the penetration of contact allergens, and hence the risk of becoming sensitized. Materials and methods. During 2006–2008, 3335 randomly invited 18–69-year- old adult Danes participated in a general health examination, filled out a questionnaire, and were genotyped for the R501X and 2282del4 mutations in FLG. Results. A logistic regression analysis restricted to individuals who reported atopic dermatitis and frequent episodes of hand eczema showed a strong association between FLG mutations and contact sensitization to allergens other than nickel (odds ratio 5.71; 95% confidence interval 1.31 – 24.94). In participants without dermatitis, no association was found between contact sensitization and FLG mutations. Conclusion. FLG mutation carriers with self-reported dermatitis have an increased risk of contact sensitization to substances other than nickel, whereas FLG mutations alone may not, or may only slightly, increase the risk of sensitization. Key words: contact sensitization; dermatitis; epidemiology; filaggrin gene; general population. Correspondence: Jacob P. Thyssen, Department of Dermato-Allergology, National Allergy Research Centre, Copenhagen University Hospital Gentofte, University of Copenhagen, Niels Andersens Vej 65, 2900 Hellerup, Denmark. Tel: +45 3977 7307; Fax: +45 3977 7118. E-mail: jacob.p.thyssen@regionh.dk Conflicts of interest: The authors have no conflict of interest to disclose. Funding: the Danish Board of Health, the Danish Environmental Protection Agency, the Copenhagen County Research Foundation, the Aase and Einar Danielsens Foundation, the Hørslev Foundation, the Velux Foundation, ALK- Abell ´ o A/S, Denmark, and the Danish Scientific Research Council. Also, MEKOS Laboratories, Denmark kindly donated some of the TRUE Tests. Accepted for publication 6 October 2012 Filaggrin proteins are crucial for skin barrier functions, as they guarantee the alignment of keratin filaments in the corneocytes and hydrate the stratum corneum. Successful genotyping of the filaggrin gene (FLG) showed that loss-of-function mutations were not only very prevalent in European and Asian races, but also caused xerosis and increased the risk of dermatitis, owing to lower filaggrin and filaggrin metabolite levels (1, 2). Moreover, T helper cell type 2-driven immune responses, characterized by, for example, elevated interleukin (IL)-4, IL-13, IL- 17A, IL-22 and IL-25 levels, may reduce filaggrin levels, and cause secondary impairment of the skin barrier (3 – 6).  2013 John Wiley & Sons A/S Contact Dermatitis, 68, 273–276 273