2. Academic Validation
  3. A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility

A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility

  • Am J Hum Genet. 2015 Apr 2;96(4):565-80. doi: 10.1016/j.ajhg.2015.02.009.
F David Carmona 1,  Sarah L Mackie 2,  Jose-Ezequiel Martín 3,  John C Taylor 4,  Augusto Vaglio 5,  Stephen Eyre 6,  Lara Bossini-Castillo 3,  Santos Castañeda 7,  Maria C Cid 8,  José Hernández-Rodríguez 8,  Sergio Prieto-González 8,  Roser Solans 9,  Marc Ramentol-Sintas 9,  M Francisca González-Escribano 10,  Lourdes Ortiz-Fernández 10,  Inmaculada C Morado 11,  Javier Narváez 12,  José A Miranda-Filloy 13,  Spanish GCA Group,  Lorenzo Beretta 14,  Claudio Lunardi 15,  Marco A Cimmino 16,  Davide Gianfreda 17,  Daniele Santilli 18,  Giuseppe A Ramirez 19,  Alessandra Soriano 20,  Francesco Muratore 21,  Giulia Pazzola 21,  Olga Addimanda 21,  Cisca Wijmenga 22,  Torsten Witte 23,  Jan H Schirmer 24,  Frank Moosig 24,  Verena Schönau 25,  Andre Franke 26,  Øyvind Palm 27,  Øyvind Molberg 27,  Andreas P Diamantopoulos 28,  Simon Carette 29,  David Cuthbertson 30,  Lindsy J Forbess 31,  Gary S Hoffman 32,  Nader A Khalidi 33,  Curry L Koening 34,  Carol A Langford 32,  Carol A McAlear 35,  Larry Moreland 36,  Paul A Monach 37,  Christian Pagnoux 29,  Philip Seo 38,  Robert Spiera 39,  Antoine G Sreih 35,  Kenneth J Warrington 40,  Steven R Ytterberg 40,  Peter K Gregersen 41,  Colin T Pease 42,  Andrew Gough 43,  Michael Green 44,  Lesley Hordon 45,  Stephen Jarrett 46,  Richard Watts 47,  Sarah Levy 48,  Yusuf Patel 49,  Sanjeet Kamath 50,  Bhaskar Dasgupta 51,  Jane Worthington 6,  Bobby P C Koeleman 52,  Paul I W de Bakker 53,  Jennifer H Barrett 4,  Carlo Salvarani 21,  Peter A Merkel 35,  Miguel A González-Gay 54,  Ann W Morgan 4,  Javier Martín 3
Affiliations

Affiliations

  • 1 Instituto de Parasitología y Biomedicina "López-Neyra," CSIC, PTS Granada, Granada 18016, Spain. Electronic address: dcarmona@ipb.csic.es.
  • 2 Leeds Institute of Rheumatic and Musculoskeletal Medicine and NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds LS7 4SA, UK.
  • 3 Instituto de Parasitología y Biomedicina "López-Neyra," CSIC, PTS Granada, Granada 18016, Spain.
  • 4 School of Medicine and NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds LS9 7TF, UK.
  • 5 Unit of Nephrology, University Hospital of Parma, Parma 43126, Italy.
  • 6 NIHR Manchester Musculoskeletal Biomedical Research Unit, Manchester Academy of Health Sciences, Manchester, UK; Arthritis Research UK Epidemiology Unit, University Of Manchester, Manchester M13 9NT, UK.
  • 7 Department of Rheumatology, Hospital de la Princesa, IIS-Princesa, Madrid 28006, Spain.
  • 8 Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
  • 9 Autoimmune Systemic Diseases Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona 08035, Spain.
  • 10 Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla 41013, Spain.
  • 11 Department of Rheumatology, Hospital Clínico San Carlos, Madrid 28040, Spain.
  • 12 Department of Rheumatology, Hospital Universitario de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona 08907, Spain.
  • 13 Department of Rheumatology, Hospital Xeral-Calde, Lugo 27004, Spain.
  • 14 Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan 20122, Italy.
  • 15 Department of Medicine, Universita degli Studi di Verona, Verona 37134, Italy.
  • 16 Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova 16132, Italy.
  • 17 Department of Clinical and Experimental Medicine, University of Parma, School of Medicine, Parma 43126, Italy.
  • 18 Unit of Internal Medicine and Rheumatology, University Hospital of Parma, Parma 43126, Italy.
  • 19 Unit of Internal Medicine and Immunology, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan 20132, Italy.
  • 20 Department of Clinical Medicine and Rheumatology, Campus Bio-Medico University, Rome 00128, Italy.
  • 21 Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia 42123, Italy.
  • 22 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700, the Netherlands.
  • 23 Hannover Medical School, Hannover 30625, Germany.
  • 24 Vasculitis Clinic, Klinikum Bad Bramstedt & University Hospital of Schleswig Holstein, Bad Bramstedt 24576, Germany.
  • 25 Department of Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen 91054, Germany.
  • 26 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany.
  • 27 Department of Rheumatology, Oslo University Hospital, Oslo 0424, Norway.
  • 28 Department of Rheumatology, Hospital of Southern Norway Trust, Kristiansand 4604, Norway.
  • 29 Division of Rheumatology, Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada.
  • 30 Department of Biostatistics, University of South Florida, Tampa, FL 33612, USA.
  • 31 Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 32 Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
  • 33 Division of Rheumatology, St. Joseph's Healthcare, McMaster University, Hamilton, ON L8N 1Y2, Canada.
  • 34 Division of Rheumatology, University of Utah, Salt Lake City, UT 84132, USA.
  • 35 Penn Vasculitis Center, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 36 Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
  • 37 Section of Rheumatology, Boston University School of Medicine, Boston, MA 02118, USA.
  • 38 Division of Rheumatology, Johns Hopkins University, Baltimore, MD 21224, USA.
  • 39 Department of Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA.
  • 40 Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
  • 41 The Feinstein Institute for Medical Research, North Shore - Long Island Jewish Health System, Manhasset, NY 11030, USA.
  • 42 Department of Rheumatology, Leeds Teaching Hospitals NHS Trust, Leeds LS7 4SA, UK.
  • 43 Department of Rheumatology, Harrogate and District NHS Foundation Trust, Harrogate HG2 7SX, UK.
  • 44 Department of Rheumatology, York Teaching Hospital NHS Foundation Trust, York YO31 8HE, UK.
  • 45 Department of Rheumatology, Mid Yorkshire Hospitals NHS Trust, Dewsbury and District Hospital, Dewsbury WF13 4HS, UK.
  • 46 Department of Rheumatology, Mid Yorkshire Hospitals NHS Trust, Pinderfields Hospital, Wakefield WF1 4DG, UK.
  • 47 Department of Rheumatology, Ipswich Hospital NHS Trust, Ipswich IP4 5PD, UK.
  • 48 Department of Rheumatology, Croydon Health Service NHS Trust, Croydon CR7 7YE, UK.
  • 49 Department of Rheumatology, Hull and East Yorkshire NHS Trust, Hull HU3 2JZ, UK.
  • 50 Department of Rheumatology, Staffordshire and Stoke-on-Trent Partnership NHS Trust, Staffordshire ST6 7AG, UK.
  • 51 Department of Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea SS0 0RY, UK.
  • 52 Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.
  • 53 Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands; Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.
  • 54 Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander 39008, Spain.
PMID: 25817017 DOI: 10.1016/j.ajhg.2015.02.009
Abstract

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II Amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed Other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.

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