title: A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility.
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.
authors: Instituto de Parasitología y Biomedicina "López-Neyra," CSIC, PTS Granada, Granada 18016, Spain. Electronic address: dcarmona@ipb.csic.es.
authors: F David
authors: FD
authors: Carmona
authors: Leeds Institute of Rheumatic and Musculoskeletal Medicine and NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds LS7 4SA, UK.
authors: Sarah L
authors: SL
authors: Mackie
authors: Instituto de Parasitología y Biomedicina "López-Neyra," CSIC, PTS Granada, Granada 18016, Spain.
authors: Jose-Ezequiel
authors: JE
authors: Martín
authors: School of Medicine and NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds LS9 7TF, UK.
authors: John C
authors: JC
authors: Taylor
authors: Unit of Nephrology, University Hospital of Parma, Parma 43126, Italy.
authors: Augusto
authors: A
authors: Vaglio
authors: 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.
authors: Stephen
authors: S
authors: Eyre
authors: Instituto de Parasitología y Biomedicina "López-Neyra," CSIC, PTS Granada, Granada 18016, Spain.
authors: Lara
authors: L
authors: Bossini-Castillo
authors: Department of Rheumatology, Hospital de la Princesa, IIS-Princesa, Madrid 28006, Spain.
authors: Santos
authors: S
authors: Castañeda
authors: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors: Maria C
authors: MC
authors: Cid
authors: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors: José
authors: J
authors: Hernández-Rodríguez
authors: Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors: Sergio
authors: S
authors: Prieto-González
authors: Autoimmune Systemic Diseases Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona 08035, Spain.
authors: Roser
authors: R
authors: Solans
authors: Autoimmune Systemic Diseases Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona 08035, Spain.
authors: Marc
authors: M
authors: Ramentol-Sintas
authors: Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla 41013, Spain.
authors: M Francisca
authors: MF
authors: González-Escribano
authors: Department of Immunology, Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Sevilla 41013, Spain.
authors: Lourdes
authors: L
authors: Ortiz-Fernández
authors: Department of Rheumatology, Hospital Clínico San Carlos, Madrid 28040, Spain.
authors: Inmaculada C
authors: IC
authors: Morado
authors: Department of Rheumatology, Hospital Universitario de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Barcelona 08907, Spain.
authors: Javier
authors: J
authors: Narváez
authors: Department of Rheumatology, Hospital Xeral-Calde, Lugo 27004, Spain.
authors: José A
authors: JA
authors: Miranda-Filloy
authors: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan 20122, Italy.
authors: Lorenzo
authors: L
authors: Beretta
authors: Department of Medicine, Universita degli Studi di Verona, Verona 37134, Italy.
authors: Claudio
authors: C
authors: Lunardi
authors: Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova 16132, Italy.
authors: Marco A
authors: MA
authors: Cimmino
authors: Department of Clinical and Experimental Medicine, University of Parma, School of Medicine, Parma 43126, Italy.
authors: Davide
authors: D
authors: Gianfreda
authors: Unit of Internal Medicine and Rheumatology, University Hospital of Parma, Parma 43126, Italy.
authors: Daniele
authors: D
authors: Santilli
authors: Unit of Internal Medicine and Immunology, IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan 20132, Italy.
authors: Giuseppe A
authors: GA
authors: Ramirez
authors: Department of Clinical Medicine and Rheumatology, Campus Bio-Medico University, Rome 00128, Italy.
authors: Alessandra
authors: A
authors: Soriano
authors: Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia 42123, Italy.
authors: Francesco
authors: F
authors: Muratore
authors: Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia 42123, Italy.
authors: Giulia
authors: G
authors: Pazzola
authors: Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia 42123, Italy.
authors: Olga
authors: O
authors: Addimanda
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700, the Netherlands.
authors: Cisca
authors: C
authors: Wijmenga
authors: Hannover Medical School, Hannover 30625, Germany.
authors: Torsten
authors: T
authors: Witte
authors: Vasculitis Clinic, Klinikum Bad Bramstedt & University Hospital of Schleswig Holstein, Bad Bramstedt 24576, Germany.
authors: Jan H
authors: JH
authors: Schirmer
authors: Vasculitis Clinic, Klinikum Bad Bramstedt & University Hospital of Schleswig Holstein, Bad Bramstedt 24576, Germany.
authors: Frank
authors: F
authors: Moosig
authors: Department of Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen 91054, Germany.
authors: Verena
authors: V
authors: Schönau
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany.
authors: Andre
authors: A
authors: Franke
authors: Department of Rheumatology, Oslo University Hospital, Oslo 0424, Norway.
authors: Øyvind
authors: Ø
authors: Palm
authors: Department of Rheumatology, Oslo University Hospital, Oslo 0424, Norway.
authors: Øyvind
authors: Ø
authors: Molberg
authors: Department of Rheumatology, Hospital of Southern Norway Trust, Kristiansand 4604, Norway.
authors: Andreas P
authors: AP
authors: Diamantopoulos
authors: Division of Rheumatology, Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada.
authors: Simon
authors: S
authors: Carette
authors: Department of Biostatistics, University of South Florida, Tampa, FL 33612, USA.
authors: David
authors: D
authors: Cuthbertson
authors: Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Lindsy J
authors: LJ
authors: Forbess
authors: Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors: Gary S
authors: GS
authors: Hoffman
authors: Division of Rheumatology, St. Joseph's Healthcare, McMaster University, Hamilton, ON L8N 1Y2, Canada.
authors: Nader A
authors: NA
authors: Khalidi
authors: Division of Rheumatology, University of Utah, Salt Lake City, UT 84132, USA.
authors: Curry L
authors: CL
authors: Koening
authors: Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors: Carol A
authors: CA
authors: Langford
authors: Penn Vasculitis Center, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Carol A
authors: CA
authors: McAlear
authors: Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors: Larry
authors: L
authors: Moreland
authors: Section of Rheumatology, Boston University School of Medicine, Boston, MA 02118, USA.
authors: Paul A
authors: PA
authors: Monach
authors: Division of Rheumatology, Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada.
authors: Christian
authors: C
authors: Pagnoux
authors: Division of Rheumatology, Johns Hopkins University, Baltimore, MD 21224, USA.
authors: Philip
authors: P
authors: Seo
authors: Department of Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA.
authors: Robert
authors: R
authors: Spiera
authors: Penn Vasculitis Center, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Antoine G
authors: AG
authors: Sreih
authors: Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors: Kenneth J
authors: KJ
authors: Warrington
authors: Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors: Steven R
authors: SR
authors: Ytterberg
authors: The Feinstein Institute for Medical Research, North Shore - Long Island Jewish Health System, Manhasset, NY 11030, USA.
authors: Peter K
authors: PK
authors: Gregersen
authors: Department of Rheumatology, Leeds Teaching Hospitals NHS Trust, Leeds LS7 4SA, UK.
authors: Colin T
authors: CT
authors: Pease
authors: Department of Rheumatology, Harrogate and District NHS Foundation Trust, Harrogate HG2 7SX, UK.
authors: Andrew
authors: A
authors: Gough
authors: Department of Rheumatology, York Teaching Hospital NHS Foundation Trust, York YO31 8HE, UK.
authors: Michael
authors: M
authors: Green
authors: Department of Rheumatology, Mid Yorkshire Hospitals NHS Trust, Dewsbury and District Hospital, Dewsbury WF13 4HS, UK.
authors: Lesley
authors: L
authors: Hordon
authors: Department of Rheumatology, Mid Yorkshire Hospitals NHS Trust, Pinderfields Hospital, Wakefield WF1 4DG, UK.
authors: Stephen
authors: S
authors: Jarrett
authors: Department of Rheumatology, Ipswich Hospital NHS Trust, Ipswich IP4 5PD, UK.
authors: Richard
authors: R
authors: Watts
authors: Department of Rheumatology, Croydon Health Service NHS Trust, Croydon CR7 7YE, UK.
authors: Sarah
authors: S
authors: Levy
authors: Department of Rheumatology, Hull and East Yorkshire NHS Trust, Hull HU3 2JZ, UK.
authors: Yusuf
authors: Y
authors: Patel
authors: Department of Rheumatology, Staffordshire and Stoke-on-Trent Partnership NHS Trust, Staffordshire ST6 7AG, UK.
authors: Sanjeet
authors: S
authors: Kamath
authors: Department of Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea SS0 0RY, UK.
authors: Bhaskar
authors: B
authors: Dasgupta
authors: 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.
authors: Jane
authors: J
authors: Worthington
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.
authors: Bobby P C
authors: BP
authors: Koeleman
authors: 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.
authors: Paul I W
authors: PI
authors: de Bakker
authors: School of Medicine and NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds LS9 7TF, UK.
authors: Jennifer H
authors: JH
authors: Barrett
authors: Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia 42123, Italy.
authors: Carlo
authors: C
authors: Salvarani
authors: Penn Vasculitis Center, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Peter A
authors: PA
authors: Merkel
authors: Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander 39008, Spain.
authors: Miguel A
authors: MA
authors: González-Gay
authors: School of Medicine and NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds LS9 7TF, UK.
authors: Ann W
authors: AW
authors: Morgan
authors: Instituto de Parasitología y Biomedicina "López-Neyra," CSIC, PTS Granada, Granada 18016, Spain.
authors: Javier
authors: J
authors: Martín
mesh_terms: D015331:Cohort Studies; D005802:Genes, MHC Class II / Q000235:genetics*; D056726:Genetic Association Studies; D005838:Genotype; D013700:Giant Cell Arteritis / Q000235:genetics*; D006801:Humans; D020412:Multifactorial Inheritance / Q000235:genetics*; D015999:Multivariate Analysis; D016017:Odds Ratio; D044465:White People / Q000235:genetics