Acta Dermato-Venereologica 97-4 | Page 13

456 INVESTIGATIVE REPORT The Value of FLG Null Mutations in Predicting Treatment Response in Atopic Dermatitis: An Observational Study in Finnish Patients Tiia Maria LUUKKONEN 1,2# , Ville KIISKI 3# , Maria AHOLA 3 , Johanna MANDELIN 3 , Hannele VIRTANEN 3 , Minna PÖYHÖNEN 4,5 , Sirpa KIVIRIKKO 4 , Ida SURAKKA 1,2 , Sakari REITAMO†, Aarno PALOTIE 1,6 , Markku HELIÖVAARA 2 , Eveliina JAKKULA 4 and Anita REMITZ 3 Institute for Molecular Medicine Finland FIMM, 2 National Institute for Health and Welfare THL, 3 Skin and Allergy Hospital, 4 Clinical Genetics, University of Helsinki and Helsinki University Hospital, 5 Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland, and 6 Broad Institute of Harvard and MIT, Cambridge, MA, USA. †Deceased # These authors contributed equally to this work. 1 The contribution of FLG null mutations to predicting atopic dermatitis (AD) treatment response is not clear, nor have such mutations been studied in the Finnish population. This study tested the association of the 4 most prevalent European FLG null mutations, the 2 Finnish enriched FLG null mutations, the FLG 12-re- peat allele, and 50 additional epidermal barrier gene variants, with risk of AD, disease severity, clinical features, risk of other atopic diseases, age of onset, and treatment response in 501 patients with AD and 1,710 controls. AD, early-onset AD, palmar hyperlinea- rity, and asthma showed significant associations with the combined FLG null genotype. Disease severity and treatment response were independent of patient FLG status. Carrier frequencies of R501X, 2282del4, and S3247X were notably lower in Finns compared with reported frequencies in other populations. This data confirms FLG mutations as risk factors for AD in Finns, but also questions their feasibility as biomarkers in predicting treatment response. Key words: atopic dermatitis; filaggrin gene; skin barrier; tight junction; biomarker; treatment response. Accepted Nov 10, 2016; Epub ahead of print Nov 14, 2016 Acta Derm Venereol 2017; 97: 456–463. Corr: Anita Remitz, Department of Dermatology, Allergology and Vene- reology, Skin and Allergy Hospital, University of Helsinki and Helsinki Uni- versity Hospital, PO Box PL 160, FIN-00029 Helsinki, Finland. E-mail: [email protected] A topic dermatitis (AD; atopic eczema) is a chronic or relapsing, itchy, inflammatory skin disease with multifactorial pathogenesis and interplay of complex underlying genetic and environmental factors. The skin symptoms often prelude other manifestations of atopy: allergic rhinitis, allergic conjunctivitis, and asthma (1). The key role of epidermal barrier dysfunction in the pathogenesis of AD is undisputable: the epidermis of AD patients is characterized by a significant barrier impair- ment, contributing to increased susceptibility to bacterial and viral infections, microbial colonization, and allergic sensitizations (2, 3). Filaggrin is one of the most important proteins invol- ved in epidermal barrier homeostasis. The filaggrin gene (FLG) is a complex, highly polymorphic, and repetitive doi: 10.2340/00015555-2578 Acta Derm Venereol 2017; 97: 456–463 gene located within the epidermal differentiation com- plex on chromosome 1q21 (4). (The genomic and protein organization of FLG is shown in Fig. 1). At least 3 FLG copy number variants are recognized, with 10, 11 and 12 repeat alleles present in normal populations of Eu- ropean ethnicity (4). Some studies have suggested that extra filaggrin repeats, and thus extra filaggrin protein, may strengthen the epidermal barrier properties of the skin and consequently have a dose-dependent effect on disease severity in AD (5, 6). Prevalent FLG loss-of-function (LoF) mutations (FLG null) are the most significant and consistently replicated risk factors for AD in European (2282del4, R501X, and R2447X) and Asian (3321delA and Q2417X) populations (7–9). FLG null mutations have been associated with earlier onset of disease (10). It has been proposed that they are a risk factor only for the early-onset form of AD (11) and they seem to increase the risk of allergic rhinitis and food allergies in child- hood and adolescence (12, 13). FLG null mutations are also well-established risk factors for asthma in patients with AD, but with regard to asthma in the absence of eczema, results are conflicting (14, 15). FLG null muta- tions have been associated with palmar hyperlinearity, keratosis pilaris, hand eczema, and more persistent symptoms of AD (9, 16–19). The movement of substances between cells is regulated by tight junctions (TJ), which form the major paracellular barrier in the human epithelia (20). The permeability of TJs is regulated mainly by claudins. Claudin 1 (CLDN1) and Claudin 23 (CLDN23) expressions are reduced in AD and the reduction in CLDN1 has been shown to di- minish the integrity of TJs and correlates inversely with Th2 cytokines (21, 22). Certain mutations of CLDN1 are associated with increased risk of AD in North American populations (21). The possible roles of many other TJ proteins, and proteins involved in the structure and fun- ction of the cell envelope structure in the pathogenesis of AD are yet to be elucidated. It seems plausible that AD consists of several different endophenotypes, which may have an effect on response to treatment (23). Studies on the effect of FLG null mu- tations or other barrier gene mutations on the treatment response are sparse. This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2017 Acta Dermato-Venereologica.