Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies

David Ellinghaus; Yana Bromberg; Hu Zhang; Jun Wang; Sebastian Zeissig; Simone Lipinski; Andreas Till; Tao Jiang; Björn Stade; Eva Ellinghaus; Andreas Keller; Manuel A Rivas; Jurgita Skieceviciene; Nadezhda T Doncheva; Xiao Liu; Qing Liu; Fuman Jiang; Michael Forster; Gabriele Mayr; Mario Albrecht; Robert Häsler; Bernhard O Boehm; Jane Goodall; Carlo R Berzuini; James Lee; Vibeke Andersen; Ulla Vogel; Limas Kupcinskas; Manfred Kayser; Michael Krawczak; Susanna Nikolaus; Rinse K Weersma; Cyriel Y Ponsioen; Miquel Sans; Cisca Wijmenga; David P Strachan; Wendy L McArdle; Séverine Vermeire; Paul Rutgeerts; Jeremy D Sanderson; Christopher G Mathew; Morten H Vatn; Markus M Nöthen; Richard H Duerr; Carsten Büning; Stephan Brand; Jürgen Glas; Juliane Winkelmann; Thomas Illig; Anna Latiano; Vito Annese; Jonas Halfvarson; Mauro D'Amato; Mark J Daly; Michael Nothnagel; Tom H Karlsen; Suresh Subramani; Philip Rosenstiel; Stefan Schreiber; Miles Parkes; Andre Franke

doi:10.1053/j.gastro.2013.04.040

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Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies

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Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies

David Ellinghaus, Yana Bromberg, Hu Zhang, Jun Wang, Sebastian Zeissig, Simone Lipinski, Andreas Till, Tao Jiang, Björn Stade, Eva Ellinghaus, …

Gastroenterology (New York, N.Y. 1943), Vol.145(2), pp.339-347

08/2013

DOI: https://doi.org/10.1053/j.gastro.2013.04.040

PMCID: PMC3753067

PMID: 23624108

Abstract

Complex Disease

Whole-Exome Sequencing

Inflammatory Bowel Disease

Genome-wide association studies (GWAS) have identified 140 Crohn’s disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies. We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems. We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10−8). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10−9). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways. We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

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Title: Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies
Creators: David Ellinghaus - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Yana Bromberg - Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, New Jersey
Hu Zhang - Gastroenterology Research Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, England
Jun Wang - BGI-Shenzhen, Shenzhen, China
Sebastian Zeissig - Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany
Simone Lipinski - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Andreas Till - Section of Molecular Biology, University of California San Diego, and San Diego Center for Systems Biology, La Jolla, California
Tao Jiang - BGI-Shenzhen, Shenzhen, China
Björn Stade - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Eva Ellinghaus - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Andreas Keller - Department of Human Genetics, Saarland University, Homburg, Germany
Manuel A Rivas - Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts
Jurgita Skieceviciene - Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
Nadezhda T Doncheva - Max-Planck Institute for Informatics, Saarbrücken, Germany
Xiao Liu - BGI-Shenzhen, Shenzhen, China
Qing Liu - BGI-Shenzhen, Shenzhen, China
Fuman Jiang - BGI-Shenzhen, Shenzhen, China
Michael Forster - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Gabriele Mayr - Max-Planck Institute for Informatics, Saarbrücken, Germany
Mario Albrecht - Max-Planck Institute for Informatics, Saarbrücken, Germany
Robert Häsler - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Bernhard O Boehm - Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Medical Center Ulm, and Center of Excellence “Metabolic Disorders” Baden-Württemberg, Ulm, Germany
Jane Goodall - Department of Medicine, University of Cambridge, Cambridge, England
Carlo R Berzuini - Statistical Laboratory, Centre for Mathematical Sciences, University of Cambridge, Cambridge, England
James Lee - Gastroenterology Research Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, England
Vibeke Andersen - Medical Department, Viborg Regional Hospital, Viborg, Denmark
Ulla Vogel - National Research Centre for Working Environment, Copenhagen, Denmark
Limas Kupcinskas - Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
Manfred Kayser - Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
Michael Krawczak - Institute of Medical Informatics and Statistics, Christian-Albrechts-University of Kiel, Kiel, Germany
Susanna Nikolaus - Department of Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany
Rinse K Weersma - Department of Gastroenterology, University Medical Center Groningen, Groningen, The Netherlands
Cyriel Y Ponsioen - Department of Gastroenterology and Hepatology, Amsterdam Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Miquel Sans - Service of Digestive Diseases, Centro Médico Teknon, Barcelona, Spain
Cisca Wijmenga - Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
David P Strachan - Division of Population Health Sciences and Education, St George's, University of London, London, England
Wendy L McArdle - Avon Longitudinal Study of Parents and Children Laboratory, Department of Social and Community Medicine, University of Bristol, Bristol, England
Séverine Vermeire - Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
Paul Rutgeerts - Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
Jeremy D Sanderson - Department of Gastroenterology, Guy's & St. Thomas' National Health Service Foundation Trust, London, England
Christopher G Mathew - Division of Genetics and Molecular Medicine, King's College London, London, England
Morten H Vatn - Medical Department, Rikshospitalet University Hospital, Oslo, Norway
Markus M Nöthen - Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
Richard H Duerr - Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Carsten Büning - Department of Gastroenterology, Hepatology and Endocrinology, Charité, Campus Mitte, Berlin, Germany
Stephan Brand - Department of Medicine II, Grosshadern, Ludwig Maximilians University, Munich, Germany
Jürgen Glas - Department of Medicine II, Grosshadern, Ludwig Maximilians University, Munich, Germany
Juliane Winkelmann - Institute of Human Genetics, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
Thomas Illig - Research Unit of Molecular Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
Anna Latiano - Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Vito Annese - Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
Jonas Halfvarson - Division of Gastroenterology, Örebro University Hospital, and School of Health and Medical Sciences, Örebro University, Örebro, Sweden
Mauro D'Amato - Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
Mark J Daly - Broad Institute of Harvard and MIT, Cambridge, Massachusetts
Michael Nothnagel - Institute of Medical Informatics and Statistics, Christian-Albrechts-University of Kiel, Kiel, Germany
Tom H Karlsen - Division of Cancer, Surgery and Transplantation, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
Suresh Subramani - Section of Molecular Biology, University of California San Diego, and San Diego Center for Systems Biology, La Jolla, California
Philip Rosenstiel - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Stefan Schreiber - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Miles Parkes - Gastroenterology Research Unit, Addenbrooke's Hospital, University of Cambridge, Cambridge, England
Andre Franke - Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
Publication Details: Gastroenterology (New York, N.Y. 1943), Vol.145(2), pp.339-347
Date published: 08/2013
Publisher: Elsevier Inc
Grant note: GM069373 / National Institutes of Health FR 2821/2-1 / Deutsche Forschungsgemeinschaft BR1912/6-1 / DFG G0000934 / Medical Research Council
Academic Unit: Biochemistry and Microbiology (SEBS)
Language: English
Resource Type: Journal article
Identifiers: 991031665201604646