Ahluwalia, Tarunveer S

Bager, Peter

Ballardini, Natalia

Bergstrom, Anna

Bisgaard, Hans

Bustamante, Mariona

Bønnelykke, Klaus

Chawes, Bo Lund Krogsgaard

Curtin, John A

Custovic, Adnan

Duijts, Liesbeth

Elbert, Niels

Esplugues, Ana

Heinrich, Joachim

Herberth, Gunda

Holt, Patrick G

Hourihane, JO’B

Hu, Chen

Lau, Susanne

Lee, Young-Ae

Marenholz, Ingo

Melbye, Mads

Melén, Erik

Nijsten, Tamar

O'Sullivan, D

Pasmans, SGMA

Paternoster, Lavinia

Pennell, Craig E

Schikowski, Tamara

Simpson, Angela

Standl, Marie

Stokholm, Jakob

Thyssen, Jacob P

Torrent, Maties

von Berg, Andrea

Wang, Carol A

English

Atopic dermatitis (AD) is a prevalent inflammatory skin disease. Loss-of-function mutations in filaggrin gene (FLG) represent the strongest genetic risk factors for AD, being strongly associated with early disease onset and persistence into adulthood.1 The epidermis of individuals with mutations in FLG is fundamentally different from normal skin being characterized by increased penetration of allergens.2 Recent birth cohort studies showed a significant interaction between cat ownership at birth and mutations in FLG (R501X, 2282del4) on the development of early-onset AD.3 This finding was replicated for the 2282del4 FLG mutation in a Dutch cohort study, and extended to further associate with risk of allergic sensitization.4 We performed analyses in multiple birth cohorts to examine the consistency and overall strength of the previously observed interaction. <br/

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                          Thyssen, J. P., Ahluwalia, T. S., Paternoster, L., Ballardini, N.,Bergstrom, A., Melén, E., Chawes, B. L. K., Stokholm, J., Hourihane,JOB., O'Sullivan, D., Bager, P., Melbye, M., Bustamante, M., Torrent,M., Esplugues, A., Duijts, L., Hu, C., Elbert, N., Pasmans, SGMA., ...Bønnelykke, K. (2020). Interaction between filaggrin mutations andneonatal cat exposure in atopic dermatitis. Allergy.Peer reviewed versionLink to publication record in Explore Bristol ResearchPDF-documentThis is the author accepted manuscript (AAM). The final published version (version of record) is available onlinevia Wiley at https://onlinelibrary.wiley.com/doi/10.1111/all.14162. Please refer to any applicable terms of use ofthe publisher.University of Bristol - Explore Bristol ResearchGeneral rightsThis document is made available in accordance with publisher policies. Please cite only thepublished version using the reference above. Full terms of use are available:http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ 1  Interaction between filaggrin mutations and neonatal cat exposure in atopic dermatitis Letter to the editor  Jacob P. Thyssen1, Tarunveer S. Ahluwalia2, Lavinia Paternoster3, Natalia Ballardini4,5, Anna Bergström4, Erik Melén4,5, Bo Chawes2, Jakob Stokholm2, Jonathan O’B Hourihane6, Donnchadh M. O’Sullivan6, Peter Bager7, Mads Melbye7,8,9, Mariona Bustamante10,11,12, Maties Torrent12,13,14, Ana Esplugues12,15,16, Liesbeth Duijts17,18,, Chen Hu17,19,20, Niels J. Elbert19,20, Suzanne G.M.A. Pasmans20, Tamar E.C. Nijsten17,18,20, Andrea von Berg 21, Marie Standl 22, Tamara Schikowski23, Gunda Herberth24, Joachim Heinrich22,25,26, Young-Ae Lee27 , Ingo Marenholz27, Susanne Lau28, John A. Curtin29, Angela Simpson 29, Adnan Custovic30, Craig E. Pennell31, Carol A. Wang31, Patrick G. Holt32, Hans Bisgaard2*, Klaus Bønnelykke2*  * These authors contributed equally to the study  1) Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. 2) COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. 3) MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK. 4) Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden  5) Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden 6) Paediatrics and Child Health and INFANT Centre, University College Cork, Ireland. 7) Statens Serum Institut, Copenhagen, Denmark. 8) Department of Clinical Medicine, University of Copenhagen. 9) Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA 10) ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain 11) Universitat Pompeu Fabra (UPF), Barcelona, Spain 12) CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. 13) Ib-salut, Area de Salut de Menorca, Spain 14) Institut d'Investigació Sanitàra Illes Balears (IdISBa), Spain 15) FISABIO– Universitat Jaume I –Universitat de València Joint Research Unit of Epidemiology and Environmental Health. Avenida de Catalunya 21, 46020, Valencia, Spain 16) Nursing Department, Faculty of Nursing and Chiropody, Universitat de València, Av. Blasco Ibáñez, 13, 46010 Valencia, Spain 17) Department of Pediatrics, Division of Respiratory Medicine and Allergology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 18) Department of Pediatrics, division of Neonatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 19) The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.  20) Department of Dermatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.Research Institute, Department of Pediatrics, Marien-Hospital Wesel, Wesel, Germany 21) Research Institute, Department of Pediatrics, Marien-Hospital Wesel, Wesel, Germany 22) Institute of Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany 23) IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany 24) Department of Environmental Immunology/Core Facility Studies, Helmholtz Centre for Environmental Research – UFZ, Leipzig, Germany 25) Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, Ludwig Maximilian University (LMU), Munich, Germany  2  26) Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. 27) Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Center of MDC and Charité Universitätsmedizin Berlin, Berlin, Germany 28) Department of Pediatrics, Division of Pneumology, Immunology Charité, Universitätsmedizin Berlin, Berlin, Germany  29) Division of Infection Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester Academic Health Science Centre, and Manchester University NHS Foundation Trust  30) Section of Paediatrics, Department of Medicine, Imperial College London, London, United Kingdom  31) School of Medicine and Public Health, Faculty of Medicine and Health, University of Newcastle, Callaghan, New South Wales, Australia  32) Telethon Kids Institute, University of Western Australia, Nedlands, Australia  Total word count: 998  Number of figures/tables: 2  Number of supplementary figure/tables: 3  Number of references: 9  Running head: Interaction between FLG mutations and neonatal cat exposure in AD  Funding sources: Please see supplementary information. Conflicts of interests: The authors have no relevant conflict of interest to disclose.  Prior presentations: The content has not been published previously and is not otherwise submitted for publication.  Correspondence:  Professor Klaus Bønnelykke, MD, PhD COPSAC, Copenhagen Prospective Studies on Asthma in Childhood Herlev and Gentofte Hospital Ledreborg Alle 34 2820 Gentofte Denmark E-mail: kb@copsac.com Website: www.copsac.com  3         4  Introduction Atopic dermatitis (AD) is a prevalent inflammatory skin disease. Loss-of-function mutations in filaggrin gene (FLG) represent the strongest genetic risk factors for AD, being strongly associated with early disease onset and persistence into adulthood.1 The epidermis of individuals with mutations in FLG is fundamentally different from normal skin being characterized by increased penetration of allergens.2   Recent birth cohort studies showed a significant interaction between cat ownership at birth and mutations in FLG (R501X, 2282del4) on the development of early-onset AD.3 This finding was replicated for the 2282del4 FLG mutation in a Dutch cohort study, and extended to further associate with risk of allergic sensitization.4 We performed analyses in multiple birth cohorts to examine the consistency and overall strength of the previously observed interaction.   Materials and methods  Cohorts, exposures, genotypes and phenotypes Consortium collaborators were invited to participate in the study, 5 and 13 birth cohorts provided data on cat exposure,  AD, and filaggrin mutations (Table 1 and Supplementary Table 1+2). All cohorts had information on the most common mutations in FLG, R501X and 2282del4, and the majority also had information on R2447X and S3247X (Table 1). Heterozygous, compound heterozygous and homozygous FLG mutation carriers were pooled as mutation carriers. Cat ownership/exposure was based on questionnaires or interviews. AD diagnoses were based on questionnaires in 11 cohorts, and by physician examination in 3 cohorts (COPSAC2000, COPSAC2010 and MAAS). For further details, please see supplementary information online.   Statistical analysis and outcomes The predetermined primary outcome was AD onset before one year of age (‘ADearly’).Secondary outcomes included i) current AD at seven years of age or the year of assessment closest to, but before, 7 years (‘ADcurrent’), and ii) a history of AD during the first 7 years of life, or last year of assessment (ADever). For further details, please see supplementary information online.   5   Results A total of 22,133 children were studied (Table 1 and supplementary Table 1). The median prevalence (range) of mutations in FLG was 9.4% (4.6-12.3), cat exposure 15% (7.9-29.6), ADearly), ADcurrent, and ADever, respectively, 18% (9.7-34.6), 13.9% (3.9-20), and 39.5% (20.4-67). There was no interaction between FLG mutations and cat exposure on the risk of the primary outcome ‘ADearly’ (OR 1.10 (95% CI 0.86-1.43), I2% 0.0), (Figure 1 and Table 1). There was a statistically significant interaction for the secondary outcome of having AD at last time of examination or questioning at 7 years of age (ADcurrent), in the direction of increased risk of AD from cat exposure in children with FLG mutations (OR 1.36 (95% CI 1.02-1.82) I2% 8.6), but this was not statistically significant after adjustment for multiple testing. The FLG-stratified analyses showed a trend towards cat exposure being a risk factor in children with FLG mutations and a protective factor in children without FLG mutations (Figure 1 and Supplementary Table 3). No interaction was found for the other secondary outcome ‘ADever’ (OR 1.06 (95% CI 0.82-1.37), I2%  0.0)  Discussion We found no interaction between cat exposure in infancy and mutations in FLG on ‘early-onset AD’ or ‘AD ever’. A nominally significant interaction in the expected direction was found for the secondary outcome ‘current AD’ at 7 years of age, but this did not survive adjustment for multiple testing.  A particular study strength is the large number of independent birth cohorts with prospective assessment of exposure and outcomes. Most cohorts had genotype information for the 4 most common FLG mutations ensuring a high degree of correct classification. AD diagnoses were based on questionnaire data in most  cohorts, potentially reducing diagnostic specificity. Since AD is a chronic and relapsing disease, short episodes of other eczemas, e.g. due to irritant or allergic contact dermatitis, may be suspected of being AD by parents and caregivers, in particular in the first years of life where flexural accentuation is not yet occurring. One may argue that AD measured at 7 years of age is expected to have a higher specificity due to flexural involvement. 6. Notably, the high prevalence of early AD in some cohorts could mask a true cat exposure-FLG mutation  6  interaction. Cat exposure was only assessed around birth, and it is possible that later exposure to cat could have an unmeasured effect on AD. Similar, the extent of cat exposure might vary between studies and families. Other environmental factors were not included since covariate availability differed between the cohorts. Reverse causality cannot be excluded, as families who had experienced atopic disease might have avoided having pets to prevent allergic disease in their (next) child. However, one would expect families with FLG mutations, and thereby increased risk of eczema, to avoid cat ownership, which would tend towards an apparent protective effect of having a cat.   No association between cat ownership and AD was found in another meta-analysis of 13 studies (relative risk 0.94 (95%CI 0.76-1.16)).7 When a compelling gene-environment interaction was observed between FLG mutations and cat ownership on the risk of early-onset AD in birth cohorts, it raised the possibility that preventive measures against pediatric AD could be identified by taking the genetic susceptibility into account.3, 4 The COPSAC2000 study, which provided the basis for the previous report of interaction between cat and FLG mutations, 3 benefited from close follow-up of children, and  high AD diagnostic accuracy, whereas most birth cohorts in the present meta-analysis used questionnaires, potentially leading to misclassification.  No pathomechanism has been established for the proposed association between cat ownership and AD in FLG mutation carriers. Possibly, very small cat allergens might penetrate into the viable layers of the epidermis, where they can exert immune effects.8 Previous studies demonstrating increased risk of peanut allergy FLG mutation carriers, also suggest increased peanut allergen skin penetration. 9 Another explanation could be an effect of cat exposure on the gut microbiome of mothers and children. However, the absence of filaggrin protein expression in the gut argues against this.   In conclusion, this meta-analysis could not confirm an interaction between cat exposure in infancy and FLG mutations on development of early-onset AD. Gene-environment interactions remain largely unknown.    7    Reference List   (1)  Barker JN, Palmer CN, Zhao Y, Liao H, Hull PR, Lee SP, et al. Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J Invest Dermatol 2007 Mar;127(3):564-7.  (2)  Thyssen JP, Kezic S. Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 2014 Oct;134(4):792-9.  (3)  Bisgaard H, Simpson A, Palmer CN, Bonnelykke K, McLean I, Mukhopadhyay S, et al. Gene-environment interaction in the onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by neonatal cat exposure. PLoS Med 2008 Jun 24;5(6):e131.  (4)  Schuttelaar ML, Kerkhof M, Jonkman MF, Koppelman GH, Brunekreef B, de Jongste JC, et al. Filaggrin mutations in the onset of eczema, sensitization, asthma, hay fever and the interaction with cat exposure. Allergy 2009 Dec;64(12):1758-65.  (5)  Middeldorp CM, Felix JF, Mahajan A, McCarthy MI. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia: design, results and future prospects. Eur J Epidemiol 2019 Mar 18.  (6)  Paternoster L, Savenije OEM, Heron J, Evans DM, Vonk JM, Brunekreef B, et al. Identification of atopic dermatitis subgroups in children from 2 longitudinal birth cohorts. J Allergy Clin Immunol 2018 Mar;141(3):964-71.  (7)  Pelucchi C, Galeone C, Bach JF, La VC, Chatenoud L. Pet exposure and risk of atopic dermatitis at the pediatric age: a meta-analysis of birth cohort studies. J Allergy Clin Immunol 2013 Sep;132(3):616-22.  (8)  Scharschmidt TC, Man MQ, Hatano Y, Crumrine D, Gunathilake R, Sundberg JP, et al. Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens. J Allergy Clin Immunol 2009 Sep;124(3):496-506, 506.  (9)  Brown SJ, Asai Y, Cordell HJ, Campbell LE, Zhao Y, Liao H, et al. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol 2011 Mar;127(3):661-7.     8  Table 1. Baseline characteristics of participants in birth cohorts.   *INMA sub cohorts: VAL, SAB, MEN  ** please see supplementary Table 1 for further details.  Cohort   ALSPAC BAMSE Baseline COPSAC 2000 COPSAC 2010 DNBC Generation R GINIplus INMA* LISA MAS MAAS RAINE Cohort inclusion criteria Children from the general population Children from the general population Children from the general population Children born from mothers with asthma Children from the general population Children from the general population Children from the general population Children from the general population Children from the general population Children from the general population Children from the general population Children from the general population Children from the general population Study year baseline 1991-1992 1994-1996 2008 2000 2010 1996-2001 2002-2006 1995-98 1997-2006** 1997-99 1990 1996-1997 1989-1991 Filaggrin mutations genotyped R501X, 2282del4, R2447X, S3247X R501X, 2282del4, R2447X R501X, 2282del4, R2447X, S3247X R501X, 2282del4, R2447X, S3247X R501X, 2282del4, R2447X, S3247X R501X, 2282del4, R2447X, S3247X R501X, 2282del4, R2447X, S3247X R501X, 2282del4 R501X, 2282del4, R2447X, S3247X R501X, 2282del4 R501X, 2282del4, R2447X, S3247X R501X; 2282delL4, R3247X, R2447X R501X, 2282del4, S3247X, rs138726443 Proportion with FLG mutations  11% (834/7743) 7.2% (138/1906) 10.8% (146/1344) 12.3% (49/396) 10.3% (72/700) 9.7% (91/935) 9.4% (268/2849) 7.0% (104/1490) 4.6% (28/606) 7.0% (69/987) 9.7%  (79/813) 10.1%  (87/864 9.3% (140/1500) Basis for atopic dermatitis diagnosis Questionnaire Questionnaire Questionnaire  and clinical diagnosis Clinical diagnosis Clinical diagnosis Questionnaire Questionnaire Questionnaire Questionnaire Questionnaire Questionnaire  and clinical diagnosis Questionnaire Questionnaire AD 'early onset (≤1y)'  18% (1368/7743) 16.9% (323/1906) 22.7% (292/1282) 25.3% (100/396) 11.1% (78/700) 14.7%  (137/935) 21.6%  (545/2521) 11.3% (167/1477) 31.7% (192/606) 9.7% (94/973) 14.14%  (115/813) 34.6% (160/462) 22.8% (341/1498) AD 'current'  20% (1270/6402) 17.2% (327/1896) 15.2% (178/1168) 13.9% (55/396) 13.6% (95/700) 6.8%  (65/963) 18.6%  (496/2658) 5.93%  (77/1298) 19.5% (118/604) 3.9% (32/825) 7.5% ( 58/773) 14.1%  (96/681) 13.3% (184/1386) AD 'ever (0-7 y)'  67% (4367/6501) 39.5% (743/1878) 26.3% (354/1344) 42.2% (175/396) 27.6% (193/700) 20.4%  (196/963) 41.4% (1180/2849) 35.3% (447/1266) 49.6% (307/618) 32.6%  (269/826) 36.2%  (294/813) 60.7% (306/504) 39.7% (596/1500) AD assessment time-points 6, 18, 30, 42, 57, 69, 81 months 1, 2, 4 and 8 years 6, 12 and 24 months 1 month, and then every 6 months. 1 month, and then every 6 months. 6 and 18 month, and 7 years 6 months, and 1, 2, 3, 4 and 6 years 1, 2, 3, 4, 6 and 10 years 1, 2, and 4 years 6, 12, 18, 24 months and 4, 6 and 10 years 1, 3, 6, 12, 18, 24 month and then yearly 1,3,5,8 years 1, 3, 5, 8 years Child age at cat exposure assessment During pregnancy At baseline (3 months) and/or 1 year follow-up. 6 months and 12 months Birth Birth 18 months age < 1 year) 1 year 1 year 3 months and 1 year 3 months Birth 1 year Early life cat exposure %  29.6 10.6** 8.8 15 20 16.4-22.4 ** 25.3 7.9 11.5 12.2 12.7 20.5 18  9   Figure 1. Interaction between cat exposure and common FLG mutations in relation to a) Early onset atopic dermatitis, b) Current atopic dermatitis and c) atopic dermatitis in the first 7 years of life.         

Interaction between filaggrin mutations and neonatal cat exposure in atopic dermatitis

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Interaction between filaggrin mutations and neonatal cat exposure in atopic dermatitis

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