ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 880

An Immunochip Study Confirms a Strong Contribution of HLA Class I and II Genes in the Susceptibility to Giant Cell Arteritis

Francisco David Carmona1, Sarah Mackie2, Jose Ezequiel Martin1, John Taylor2, Augusto Vaglio3, Lara Bossini-Castillo1, Santos Castañeda4, Maria C. Cid5, José Hernández-Rodríguez6, Roser Solans7, Ricardo Blanco8, Lorenzo Beretta9, Claudio Lunardi10, Marco A. Cimmino11, Cisca Wijmenga12, Torsten Witte13, Julia Holle14, Frank Moosig14, Verena Schönau15, Andre Franke16, Øyvind Palm17, Andreas P. Diamantopoulos18, Benedicte A. Lie19, Simon Carette20, David Cuthbertson21, Gary S. Hoffman22, Nader A. Khalidi23, Curry L. Koening24, Carol A. Langford25, Carol McAlear26, Larry Moreland27, Paul A. Monach28, Christian Pagnoux20, Philip Seo29, Antoine G. Sreih30, Kenneth J. Warrington31, Steven R. Ytterberg31, Colin T. Pease32, Andrew Gough33, Michael Green34, Lesley Hordon35, Stephen Jarrett36, Richard Watts37, Sarah Levy38, Yusuf Patel39, Sanjeet Kamath40, Bhaskar Dasgupta41, Paul IW. de Bakker42, Bobby P.C. Koeleman42, Jennifer H. Barrett2, Carlo Salvarani43, Peter A. Merkel44, Miguel A. Gonzalez-Gay8, Ann W. Morgan2 and Javier Martin1, 1Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Armilla (Granada), Spain, 2NIHR-Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds, United Kingdom, 3Unit of Nephrology, University Hospital of Parma, Parma, Italy, 4Rheumatology, Hospital Universitario de La Princesa, IISP, Madrid, Spain, 5Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036- Barcelona, Spain, 6Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 7Autoimmune Systemic Diseases Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain, 8Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain, 9Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, 10Department of Medicine, Università degli Studi di Verona, Verona, Italy, 11Department of Internal Medicine, Academic Unit of Clinical Rheumatology, University of Genova, Genova, Italy, 12Department of Genetics, University Medical Hospital Groningen, University of Groningen, Groningen, Netherlands, 13Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany, 14Vasculitis Clinic, Klinikum Bad Bramstedt & University Hospital of Schleswig Holstein, Bad Bramstedt, Germany, 15Department of Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany, 16Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany, 17Department of Rheumatology, Oslo University Hospital and University of Oslo, Oslo, Norway, 18Department of Rheumatology, Hospital of Southern Norway Trust, Kristiansand, Norway, 19Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway, 20Division of Rheumatology, University of Toronto, Toronto, ON, Canada, 21Department of Biostatistics, University of South Florida, Tampa, FL, 22Center for Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, OH, 23Division of Rheumatology, St. Joseph’s Hospital, McMaster University, Hamilton, ON, Canada, 24Division of Rheumatology, University of Utah, Salt Lake City, UT, 25Center for Vasculitis Care and Research, Cleveland Clinic, Cleveland, OH, 26Division of Rheumatology, Vasculitis Center, University of Pennsylvania, Philadelphia, PA, 27Rheumatology & Clinical Immunology, Vasculitis Center, of University of Pittsburgh Medical Center, Pittsburgh, PA, 28Section of Rheumatology, Vasculitis Center, Boston University School of Medicine, Boston, MA, 29Rheumatology Division, Johns Hopkins Vasculitis Center, Johns Hopkins University, Baltimore, MD, 30Medicine/Division of Rheumatology, The University of Pennsylvania, Philadelphia, PA, 31Division of Rheumatology, Mayo Clinic, Rochester, MN, 32Department of Rheumatology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom, 33Department of Rheumatology, Harrogate and District Foundation Trust, Harrogate, United Kingdom, 34Department of Rheumatology, York Teaching Hospital NHS Foundation Trust, York, United Kingdom, 35Department of Rheumatology, Mid Yorkshire Hospitals NHS Trust, Dewsbury, United Kingdom, 36Department of Rheumatology, Mid Yorkshire Hospitals NHS Trust, Wakefield, United Kingdom, 37Department of Rheumatology, Ipswich Hospital NHS Trust, Ipswich, United Kingdom, 38Department of Rheumatology, Croydon Health Service NHS Trust, Croydon, United Kingdom, 39Department of Rheumatology, Hull and East Yorkshire NHS Trust, Hull East Yorkshire, United Kingdom, 40Department of Rheumatology, Staffordshire and Stoke-on-Trent Partnership NHS Trust, Staffordshire, United Kingdom, 41Department of Rheumatology, Southend University Hospital, Essex, United Kingdom, 42Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands, 43Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy, 44University of Pennsylvania, Philadelphia, PA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Vasculitis I

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Giant cell arteritis (GCA) is a chronic autoimmune vasculitis with an important genetic component. We aimed to identify relevant risk loci for GCA predisposition by performing a large-scale genetic analysis on this disease.

Methods:

We genotyped a large cohort of patients with GCA using the Illumina Immunochip. The study cohort was of European ancestry and comprised 1,892 cases of GCA confirmed by temporal artery biopsy or vascular/imaging and 15,306 unrelated controls from 6 different countries (Spain, UK, USA, Italy, Norway and Germany). To test for association, we compared the variation frequencies of cases and controls by logistic regression under a fixed-effects model using the three first principal components (PCs), sex, and country of origin as covariates. We also imputed the HLA region using a previously validated imputation method to perform a more comprehensive analysis of this region.

Results:

The strongest association signals were observed in the HLA region, specifically histidine at position 13 of HLA-DRB1 (P=3.46e-38, OR=1.92, 95% CI=1.74-2.12). A multivariate model including 3 amino acids (a histidine in position 13 of DRB1, a leucine in position 69 of DQA1, and a threonine in position 45 of HLA-B) explained most of HLA association with GCA. All 3 amino acids are located in the binding pocket of their corresponding HLA molecule and interact directly with the antigen. Outside the HLA region, the most highly associated SNPs were located within PTPN22 (rs2476601, P=1.73E-06, OR=1.38, 95% CI=1.21-1.58) and LRRC32 (rs10160518, P=4.39E-06, OR= 1.20, 95% CI=1.11-1.29). The latter gene is selectively expressed on Tregs.

Conclusion:

Our data provide evidence of a strong contribution of HLA Class I and II molecules to susceptibility to GCA. Regarding the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and identified LRRC32 as a putative risk factor for GCA, suggesting a possible role of Tregs in the pathophysiology of GCA.

Disclosure:

F. D. Carmona,
None;

S. Mackie,
None;

J. E. Martin,
None;

J. Taylor,
None;

A. Vaglio,
None;

L. Bossini-Castillo,
None;

S. Castañeda,
None;

M. C. Cid,
None;

J. Hernández-Rodríguez,
None;

R. Solans,
None;

R. Blanco,
None;

L. Beretta,
None;

C. Lunardi,
None;

M. A. Cimmino,
None;

C. Wijmenga,
None;

T. Witte,
None;

J. Holle,
None;

F. Moosig,
None;

V. Schönau,
None;

A. Franke,
None;

Palm,
None;

A. P. Diamantopoulos,
None;

B. A. Lie,
None;

S. Carette,
None;

D. Cuthbertson,
None;

G. S. Hoffman,
None;

N. A. Khalidi,
None;

C. L. Koening,
None;

C. A. Langford,
None;

C. McAlear,
None;

L. Moreland,
None;

P. A. Monach,
None;

C. Pagnoux,
None;

P. Seo,
None;

A. G. Sreih,
None;

K. J. Warrington,
None;

S. R. Ytterberg,
None;

C. T. Pease,
None;

A. Gough,
None;

M. Green,
None;

L. Hordon,
None;

S. Jarrett,
None;

R. Watts,
None;

S. Levy,
None;

Y. Patel,
None;

S. Kamath,
None;

B. Dasgupta,
None;

P. I. de Bakker,
None;

B. P. C. Koeleman,
None;

J. H. Barrett,
None;

C. Salvarani,
None;

P. A. Merkel,

Genentech and Biogen IDEC Inc.,

2,

Bristol-Myers Squibb,

2,

GlaxoSmithKline,

2,

Actelion Pharmaceuticals US,

2,

Actelion Pharmaceuticals US,

5,

Sanofi-Aventis Pharmaceutical,

5,

Chemocentryx,

5;

M. A. Gonzalez-Gay,
None;

A. W. Morgan,
None;

J. Martin,
None.

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