Genome-wide Comparative Analysis of Atopic Dermatitis and Psoriasis Gives Insight into Opposing Genetic Mechanisms

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Abstract

Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21–22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features.

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Most cited references 42

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Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.

Colin N A Palmer, Alan D. Irvine, Ana Terron-Kwiatkowski … (2006)

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

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Pathogenesis and clinical features of psoriasis.

Christopher EM Griffiths, Jonathan Barker (2007)

Psoriasis, a papulosquamous skin disease, was originally thought of as a disorder primarily of epidermal keratinocytes, but is now recognised as one of the commonest immune-mediated disorders. Tumour necrosis factor alpha, dendritic cells, and T-cells all contribute substantially to its pathogenesis. In early-onset psoriasis (beginning before age 40 years), carriage of HLA-Cw6 and environmental triggers, such as beta-haemolytic streptococcal infections, are major determinants of disease expression. Moreover, at least nine chromosomal psoriasis susceptibility loci have been identified. Several clinical phenotypes of psoriasis are recognised, with chronic plaque (psoriasis vulgaris) accounting for 90% of cases. Comorbidities of psoriasis are attracting interest, and include impairment of quality of life and associated depressive illness, cardiovascular disease, and a seronegative arthritis known as psoriatic arthritis. A more complete understanding of underlying pathomechanisms is leading to new treatments, which will be discussed in the second part of this Series.

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The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. III. Independent hospital validation.

H.C. WILLIAMS, P.G. JBURNEY, A.C. PEMBROKE … (1994)

In order to qualify as a case of atopic dermatitis, we propose that an individual must have an itchy skin condition plus three or more of the following: history of flexural involvement, a history of asthma/hay fever, a history of a generalized dry skin, onset of rash under the age of 2 years, or visible flexural dermatitis. When tested in an independent sample of 200 consecutive dermatology outpatients of all ages, this arrangement of the diagnostic criteria achieved 69% sensitivity and 96% specificity when validated against physician's diagnosis. Based on the findings of this first exercise, minor modifications in the wording of the criteria were undertaken, and these were tested on a sample of 114 consecutive children attending out-patient paediatric dermatology clinics. Overall discrimination improved, with a sensitivity of 85% and specificity of 96%. The simplified criteria are easy to use, take under 2 min per patient to ascertain, and do not require subjects to undress. These two independent validation studies suggest that the newly proposed criteria for atopic dermatitis perform reasonably well in hospital out-patient patients. Further validation in community settings and in developing countries is needed.

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Author and article information

Contributors

Stephan Weidinger

Sara J. Brown

Journal

Journal ID (nlm-ta): Am J Hum Genet

Journal ID (iso-abbrev): Am. J. Hum. Genet

Title: American Journal of Human Genetics

Publisher: Elsevier

ISSN (Print): 0002-9297

ISSN (Electronic): 1537-6605

Publication date PMC-release: 08 January 2015

Publication date (Print): 08 January 2015

Volume: 96

Issue: 1

Pages: 104-120

Affiliations

[1 ]Department of Dermatology, Allergology, and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany

[2 ]Department of Medicine II - Grosshadern, Ludwig-Maximilians-University (LMU), 81377 Munich, Germany

[3 ]Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte, 10117 Berlin, Germany

[4 ]Neuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland

[5 ]Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany

[6 ]Max-Delbrück-Centrum (MDC) for Molecular Medicine, Berlin-Buch, 13092 Berlin, Germany

[7 ]Pediatric Allergy, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany

[8 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany

[9 ]Research Unit of Molecular Epidemiology, German Research Center for Environmental Health, 85764 Neuherberg, Germany

[10 ]Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany

[11 ]Hannover Unified Biobank, Hannover Medical School, 30625 Hannover, Germany

[12 ]Department of Paediatric Dermatology, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland

[13 ]National Children’s Research Centre, Dublin 12, Ireland

[14 ]Department of Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland

[15 ]Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), 93042 Regensburg, Germany

[16 ]Institute of Epidemiology and PopGen Biobank, University Hospital Schleswig-Holstein, 24105 Kiel, Germany

[17 ]Dermatology and Genetic Medicine, College of Life Sciences and College of Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, UK

[18 ]Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland

[19 ]Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-5675, USA

[20 ]Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany

[21 ]Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany

[22 ]Department of Dermatology and Allergy, University of Bonn Medical Center, 53105 Bonn, Germany

[23 ]Department of Internal Medicine, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany

[24 ]Division of Genetics and Molecular Medicine, St John’s Institute of Dermatology, Kings College London, London SE1 9RT, UK

[25 ]Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, 80539 Munich, Germany

[26 ]Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London E1 4NS, UK

[27 ]Department of Biostatistics, Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109-5314, USA

[28 ]Ann Arbor Veterans Affairs Hospital, Ann Arbor, MI 48105, USA

[29 ]Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK

[30 ]Dermatology and Genetic Medicine, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK

Author notes

[∗ ]Corresponding author sweidinger@ 123456dermatology.uni-kiel.de

[∗∗ ]Corresponding author s.j.brown@ 123456dundee.ac.uk

[31]

These authors contributed equally to this work

[32]

These authors contributed equally to this work

Article

Publisher ID: S0002-9297(14)00510-2

DOI: 10.1016/j.ajhg.2014.12.004

PMC ID: 4289690

PubMed ID: 25574825

SO-VID: bf33ccf5-334d-43e3-a411-08ea689bc8ce

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

History

Date received : 5 September 2014

Date accepted : 5 December 2014

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Genome-wide Comparative Analysis of Atopic Dermatitis and Psoriasis Gives Insight into Opposing Genetic Mechanisms

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Abstract

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Genomic Prediction

Most cited references 42

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.

Pathogenesis and clinical features of psoriasis.

The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. III. Independent hospital validation.

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Cited by 64

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