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      Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 9 , 8 , 9 , 4 , 4 , 5 , 11 , 11 , 11 , 4 , 4 , 5 , 11 , 12 , 13 , 14 , 8 , 8 , 11 , 3 , 3 , 15 , 1 , 1 , 16 , 16 , 1 , 12 , 12 , 17 , the 23andMe Research Team, AAGC collaborators, BIOS consortium, LifeLines Cohort Study, 19 , 20 , 20 , 12 , 21 , 12 , 12 , 22 , 23 , 12 , 23 , 12 , 20 , 19 , 24 , 25 , 26 , 27 , 1 , 1 , 28 , 29 , 30 , 29 , 31 , 32 , 33 , 34 , 6 , 4 , 3 , 9 , 35 , 34 , 4 , 5 , 8 , 9 , 36 , 9 , 37 , 11
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          Abstract

          Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals 1, partly because of a shared genetic origin 24. To identify shared risk variants, we performed a genome-wide association study (GWAS, n=360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants ( P<3x10 -8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.

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          Most cited references21

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          GeneCards: integrating information about genes, proteins and diseases.

          M Rebhan (1997)
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            Atopic dermatitis and the atopic march revisited.

            Atopic dermatitis (AD) has become a significant public health problem because of increasing prevalence, together with increasing evidence that it may progress to other allergic phenotypes. While it is now acknowledged that AD commonly precedes other allergic diseases, a link termed 'the atopic march', debate continues as to whether this represents a causal relationship. An alternative hypothesis is that this association may be related to confounding by familial factors or phenotypes that comanifest, such as early-life wheeze and sensitization. However, there is increasing evidence from longitudinal studies suggesting that the association between AD and other allergies is independent of confounding by comanifest allergic phenotypes. The hypotheses on plausible biological mechanisms for the atopic march focus on defective skin barrier function and overexpression of inflammatory mediators released by the skin affected by AD (including thymic stromal lymphopoietin). Both human and animal studies have provided evidence supporting these potential biological mechanisms. Evidence from prevention trials is now critical to establishing a causal nature of the atopic march. An emerging area of research is investigation into environmental modifiers of the atopic march. Such information will assist in identifying secondary prevention strategies to arrest the atopic march. Despite much research into the aetiology of allergies, little progress has been made in identifying effective strategies to reduce the burden of allergic conditions. In this context, the atopic march remains a promising area of investigation. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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              Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: a population-based cohort study.

              Eczema, rhinitis, and asthma often coexist (comorbidity) in children, but the proportion of comorbidity not attributable to either chance or the role of IgE sensitisation is unknown. We assessed these factors in children aged 4-8 years. In this prospective cohort study, we assessed children from 12 ongoing European birth cohort studies participating in MeDALL (Mechanisms of the Development of ALLergy). We recorded current eczema, rhinitis, and asthma from questionnaires and serum-specific IgE to six allergens. Comorbidity of eczema, rhinitis, and asthma was defined as coexistence of two or three diseases in the same child. We estimated relative and absolute excess comorbidity by comparing observed and expected occurrence of diseases at 4 years and 8 years. We did a longitudinal analysis using log-linear models of the relation between disease at age 4 years and comorbidity at age 8 years. We assessed 16 147 children aged 4 years and 11 080 aged 8 years in cross-sectional analyses. The absolute excess of any comorbidity was 1·6% for children aged 4 years and 2·2% for children aged 8 years; 44% of the observed comorbidity at age 4 years and 50·0% at age 8 years was not a result of chance. Children with comorbidities at 4 years had an increased risk of having comorbidity at 8 years. The relative risk of any cormorbidity at age 8 years ranged from 36·2 (95% CI 26·8-48·8) for children with rhinitis and eczema at age 4 years to 63·5 (95% CI 51·7-78·1) for children with asthma, rhinitis, and eczema at age 4 years. We did longitudinal assessment of 10 107 children with data at both ages. Children with comorbidities at 4 years without IgE sensitisation had higher relative risks of comorbidity at 8 years than did children who were sensitised to IgE. For children without comorbidity at age 4 years, 38% of the comorbidity at age 8 years was attributable to the presence of IgE sensitisation at age 4 years. Coexistence of eczema, rhinitis, and asthma in the same child is more common than expected by chance alone-both in the presence and absence of IgE sensitisation-suggesting that these diseases share causal mechanisms. Although IgE sensitisation is independently associated with excess comorbidity of eczema, rhinitis, and asthma, its presence accounted only for 38% of comorbidity, suggesting that IgE sensitisation can no longer be considered the dominant causal mechanism of comorbidity for these diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                24 October 2017
                30 October 2017
                December 2017
                06 June 2018
                : 49
                : 12
                : 1752-1757
                Affiliations
                [1 ]Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
                [2 ]Epidemiology, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands
                [3 ]Department of Dermatology, Allergology and Venereology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
                [4 ]Max Delbrück Center (MDC) for Molecular Medicine, Berlin, Germany
                [5 ]Clinic for Pediatric Allergy, Experimental and Clinical Research Center of Charité Universitätsmedizin Berlin and Max Delbrück Center, Berlin, Germany
                [6 ]Research, 23andMe, Mountain View, California, USA
                [7 ]Department of Epidemiology and Biostatistics, University of Calfornia San Francisco, San Francisco, California, USA
                [8 ]Department Biological Psychology, Netherlands Twin Register , Vrije University, Amsterdam, The Netherlands
                [9 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
                [11 ]MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK
                [12 ]K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
                [13 ]Department of Thoracic Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
                [14 ]Epidemiology and Biostatistics, University of Calfornia San Francisco, San Francisco, California, USA
                [15 ]Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany
                [16 ]Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
                [17 ]Department of Pathology, Stanford University School of Medicine, Stanford, USA
                [19 ]Department of Human Genetics, University of Michigan, Ann Arbor, USA
                [20 ]Department of Internal Medicine, University of Michigan, Ann Arbor, USA
                [21 ]The HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
                [22 ]Department of Dermatology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
                [23 ]Center for Statistical Genetics, University of Michigan, Ann Arbor, USA
                [24 ]Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany
                [25 ]Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
                [26 ]Institute for Community Medicine, Study of Health in Pomerania/KEF, University Medicine Greifswald, Greifswald, Germany
                [27 ]Institute for Respiratory Health, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Australia
                [28 ]Department of Dermatology and Allergology, University-Hospital Bonn, Bonn, Germany
                [29 ]Institute of Epidemiology I, Helmholtz Zentrum Munchen - German Research Center for Environmental Health , Neuherberg, Germany
                [30 ]Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research, Munich, Germany
                [31 ]Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
                [32 ]Research Unit of Molecular Epidemiology and Institute of Epidemiology II,, Helmholtz Zentrum Munchen - German Research Center for Environmental Health , Neuherberg, Germany
                [33 ]Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health , Neuherberg, Germany
                [34 ]Division of Research, Kaiser Permanente Northern California, Oakland, California, USA
                [35 ]Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands
                [36 ]Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
                [37 ]Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, the Netherlands
                Author notes
                Corresponding author: Manuel A R Ferreira, PhD, QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Herston QLD 4029, Australia, Phone: +61 7 3845 3552, Fax: +61 7 3362 0101, manuel.ferreira@ 123456qimrberghofer.edu.au
                [10]

                Current address: GlaxoSmithKline, Stevenage, UK

                [18]

                A full list of members and affiliations appears in the Supplementary Note

                [§]

                These authors jointly supervised this work.

                Article
                EMS74439
                10.1038/ng.3985
                5989923
                29083406
                4cb24891-9048-4d05-b89b-0d8303013967

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