title: Meta-analysis identifies seven susceptibility loci involved in the atopic march.
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.
authors.affiliation: Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.|Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité University Medical Center, Berlin, Germany.
authors.forename: Ingo
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authors.affiliation: Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.|Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité University Medical Center, Berlin, Germany.
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authors.affiliation: Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.
authors.forename: Franz
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authors.lastname: Rüschendorf
authors.affiliation: Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.
authors.forename: Anja
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authors.affiliation: Population Health Research Institute, St George's, University of London, London, UK.
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authors.affiliation: Department of Dermatology, Allergology, and Venerology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Hansjörg
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authors.lastname: Baurecht
authors.affiliation: Inserm, UMR-946, F-75010 Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, F-75007 Paris, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Margaritte-Jeannin
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika
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authors.affiliation: University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands.
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authors.forename: Svetlana
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authors.affiliation: Inserm, UMR-946, F-75010 Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, F-75007 Paris, France.
authors.forename: Florence
authors.identifier: http://orcid.org/0000-0001-8361-0936
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authors.affiliation: Inserm, UMR-946, F-75010 Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, F-75007 Paris, France.
authors.forename: Emmanuelle
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authors.initials: DS
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authors.affiliation: Siberian State Medical University, Tomsk, Russia.|Research Institute of Medical Genetics, Tomsk, Russia.
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authors.affiliation: Research Institute of Medical Genetics, Tomsk, Russia.
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authors.affiliation: Department of Dermatology, Allergology, and Venerology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
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authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
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authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organisation of the Brain, Genomic Imaging, Research Centre Jülich, Jülich, Germany.
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authors.affiliation: Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.
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authors.affiliation: Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.|Max Planck Institute for Molecular Genetics, Berlin, Germany.
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authors.affiliation: Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.
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authors.initials: H
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authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
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authors.affiliation: Research Institute of Medical Genetics, Tomsk, Russia.
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authors.identifier: http://orcid.org/0000-0001-5764-1528
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authors.affiliation: Department of Pediatric Pulmonology and Pediatric Allergology, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital and GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
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authors.forename: Erik
authors.initials: E
authors.lastname: Melén
authors.affiliation: Inserm, UMR-946, F-75010 Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, F-75007 Paris, France.
authors.forename: Marie-Hélène
authors.initials: MH
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: A John
authors.initials: AJ
authors.lastname: Henderson
authors.affiliation: Max-Delbrück-Center (MDC) for Molecular Medicine, Berlin, Germany.|Clinic for Pediatric Allergy, Experimental and Clinical Research Center, Charité University Medical Center, Berlin, Germany.
authors.forename: Young Ae
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mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000293:Adolescent; D000328:Adult; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D001249:Asthma / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics; D003876:Dermatitis, Atopic / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D000091344:Filaggrin Proteins; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D016547:Kinesins / Q000235:genetics; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult
chemical_list: C570280:AP5B1 protein, human; D033942:Adaptor Proteins, Vesicular Transport; D026921:Amino Acid Transport Systems, Neutral; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C489648:EFHC1 protein, human; C480344:EMSY protein, human; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C106285:IKZF3 protein, human; C508598:IL4 protein, human; C087415:KIF3A protein, human; C087215:LRRC32 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C490319:OVOL1 protein, human; D012097:Repressor Proteins; C506212:SLC6A15 protein, human; C000592187:TMTC2 protein, human; D014157:Transcription Factors; D051740:Ikaros Transcription Factor; D015847:Interleukin-4; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D016547:Kinesins