Meta-analysis identifies seven susceptibility loci involved in the atopic march

Nature Communications - Tập 6 Số 1
Ingo Marenholz1,2, Jorge Esparza-Gordillo1,2, Franz Rüschendorf2, Anja Bauerfeind2, David P. Strachan3, Ben D. Spycher4, Hansjörg Baurecht5, Patricia Margaritte‐Jeannin6,7, Annika Sääf8, Marjan Kerkhof9, Markus Ege10, Svetlana Baltic11, Melanie C. Matheson12, Jin Li13, Sven Michel14, Wei Ang15, Wendy L. McArdle16, Andreas Arnold17, Georg Homuth18, Florence Démenais6,7, Emmanuelle Bouzigon6,7, Cilla Söderhäll19, Göran Pershagen8, Johan C. de Jongste20, Dirkje S. Postma21, Charlotte Braun‐Fahrländer22, Elisabeth Horak23, Л. М. Огородова24, В. П. Пузырев25,24, E. Yu. Bragina25, Thomas J. Hudson26, Charles Morin27, David L. Duffy28, Guy B. Marks29, Colin Robertson30, Grant W. Montgomery28, Bill Musk31, Philip J. Thompson11, Nicholas G. Martin28, Anthony James31, Patrick Sleiman13,32, Elina Toskala33, Elke Rodríguez5, Regina Fölster‐Holst5, André Franke34, Wolfgang Lieb35, Christian Gieger36, Andrea Heinzmann37, Ernst Rietschel38, Thomas Keil39,40, Sven Cichon41,42,43,44, Markus M. Nöthen41,43, Craig E. Pennell15, Peter D. Sly45, Carsten Oliver Schmidt46, Anja Matanovic1,2, Valentin Schneider-Lunitz2, Matthias Heinig47,2, Norbert Hübner2, Patrick G. Holt45,48, Susanne Lau49, Michael Kabesch14, Stephan Weidinger5, Hákon Hákonarson13,32, Manuel A. R. Ferreira28, Catherine Laprise50, Maxim B. Freidin25, Jon Genuneit51, Gerard H. Koppelman52, Erik Melén8,53, Marie‐Hélène Dizier6,7, A. John Henderson16, Young Ae Lee1,2
1Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité University Medical Center, Berlin, Germany
2Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany
3Population Health Research Institute, St George's, University of London, London, UK
4Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
5Department of Dermatology, Allergology, and Venerology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
6Inserm, UMR-946, Paris, France
7Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, Paris, France
8Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
9University of Groningen, University Medical Center Groningen, GRIAC research institute, Groningen, The Netherlands
10Dr von Hauner Children’s Hospital, Ludwig Maximilians University Munich, Member of the German Center for Lung Research (DZL), Munich, Germany
11Lung Institute of Western Australia, University of Western Australia, Perth, Australia
12Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia
13Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, USA
14Department of Pediatric Pneumology and Allergy, University Children’s Hospital Regensburg (KUNO), Regensburg, Germany
15School of Women and Infant’s Health, University of Western Australia, Perth, Australia
16School of Social and Community Medicine, University of Bristol, Bristol, UK
17Clinic and Polyclinic of Dermatology, University Medicine Greifswald, Greifswald, Germany
18Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
19Department of Biosciences and Nutrition, and Center for Innovative Medicine (CIMED), Karolinska Institutet, Stockholm, Sweden
20Department of Pediatrics, Pediatric Chest Center, Erasmus University Medical Center, Rotterdam, The Netherlands
21Department of Pulmonology and GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
22Swiss Tropical and Public Health Institute and the University of Basel, Basel, Switzerland
23Division of Pediatric Cardiology and Pulmonology, Department of Pediatrics, Innsbruck Medical University, Innsbruck, Austria
24Siberian State Medical University, Tomsk, Russia
25Research Institute of Medical Genetics, Tomsk, Russia
26Ontario Institute for Cancer Research, Toronto, Canada
27Centre de santé et de services sociaux de Chicoutimi, Saguenay, Canada
28QIMR Berghofer Medical Research Institute, Brisbane, Australia
29Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia
30Department of Respiratory Medicine, Murdoch Children’s Research Institute, Melbourne, Australia
31Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia
32Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
33Department of Otolaryngology-Head and Neck Surgery, Temple University, School of Medicine, Philadelphia, USA
34Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
35Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany
36Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
37University Children’s Hospital, Albert Ludwigs University, Freiburg, Germany
38University Children's Hospital, University of Cologne, Cologne, Germany
39Institute for Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany
40Institute of Social Medicine, Epidemiology, and Health Economics, Charité University Medical Center, Berlin, Germany
41Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
42Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland
43Institute of Human Genetics, University of Bonn, Bonn, Germany
44Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organisation of the Brain, Genomic Imaging, Research Centre Jülich, Jülich, Germany
45Queensland Children's Medical Research Institute, University of Queensland, Brisbane, Australia
46Institute for Community Medicine, Study of Health in Pomerania/KEF, University Medicine Greifswald, Greifswald, Germany
47Max Planck Institute for Molecular Genetics, Berlin, Germany
48Telethon Kids Institute, University of Western Australia, Perth, Australia
49Department of Pediatric Pneumology and Immunology, Charité University Medical Center, Berlin, Germany
50Université du Québec à Chicoutimi, Saguenay, Canada
51Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
52Department of Pediatric Pulmonology and Pediatric Allergology, University of Groningen, University Medical Center Groningen, Beatrix Children’s Hospital and GRIAC Research Institute, Groningen, The Netherlands
53Sachs’ Children’s Hospital, Stockholm, Sweden

Tóm tắt

Abstract

Eczema often precedes the development of asthma in a disease course called the ‘atopic march’. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10−8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10−9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

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