New Insights into the Pathogenesis of Giant Cell Arteritis through a Genome-Wide Association Study

Francisco David Carmona¹, Augusto Vaglio², Sarah Mackie³, José Hernández-Rodríguez⁴, Paul A. Monach⁵, Santos Castañeda⁶, Roser Solans⁷, Inmaculada C. Morado⁸, Francisco Javier Narváez⁹, Marc Ramentol-Sintas¹⁰, Colin T. Pease¹¹, Bhaskar Dasgupta¹², Richard Watts¹³, Nader A. Khalidi¹⁴, Carol A. Langford¹⁵, Steven R. Ytterberg¹⁶, Luigi Boiardi¹⁷, Lorenzo Beretta¹⁸, Marcello Govoni¹⁹, Giacomo Emmi²⁰, Francesco Bonatti²¹, Marco A. Cimmino²², Torsten Witte²³, Thomas Neumann²⁴, Julia Holle²⁵, Verena Schönau²⁶, Laurent Sailler²⁷, Thomas Papo²⁸, Julien Haroche²⁹, Alfred Mahr³⁰, Luc Mouthon³¹, Øyvind Molberg³², Andreas P Diamantopoulos³³, Alexandre E. Voskuyl³⁴, Elisabeth Brouwer³⁵, Thomas Daikeler³⁶, Christoph Berger³⁷, Eamonn S. Molloy³⁸, Lorraine O'Neill³⁹, Daniel Blockmans⁴⁰, Benedicte A. Lie⁴¹, Paul Mclaren⁴², Timothy J. Vyse⁴³, Cisca Wijmenga⁴⁴, Yannick Allanore⁴⁵, Bobby P.C. Koeleman⁴⁶, Jennifer H. Barrett⁴⁷, Maria C. Cid⁴⁸, Carlo Salvarani⁴⁹, Peter A. Merkel⁵⁰, Ann W. Morgan⁵¹, Miguel Angel González-Gay⁵², Javier Martín¹ and Spanish GCA Group, UKGCA Consortium, and Vasculitis Clinical Research Consortium, ¹Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, PTS-Granada, Granada, Spain, ²Nephrology, University Hospital of Parma, Parma, Italy, ³NIHR-Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, University of Leeds, Leeds, United Kingdom, ⁴Department of Autoimmune Diseases, Hospital Clínic University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, ⁵Rheumatology, Boston University School of Medicine, Boston, MA, ⁶Rheumatology, Hospital de la Princesa, IIS-IP, Madrid, Spain, ⁷Autoimmune Systemic Diseases Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Autonomous University of Barcelona, Spain, Barcelona, Spain, ⁸Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain, ⁹Rheumatology, Hospital Universitario de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain, ¹⁰Internal Medicine, Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain, ¹¹Rheumatology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom, ¹²Rheumatology, Southend University Hospital NHS Foundation Trust, Westcliff-on-Sea, United Kingdom, ¹³Rheumatology, Ipswich Hospital NHS Trust, Ipswich, United Kingdom, ¹⁴Rheumatology, McMaster University, Hamilton, ON, Canada, ¹⁵Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, ¹⁶Rheumatology, Mayo Clinic, Rochester, MN, ¹⁷Rheumatology Unit, Department of Internal Medicine, Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italy, ¹⁸Scleroderma Unit, Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, ¹⁹Medical Sciences, UOC of Rheumatology, University Hospital S. Anna, Cona Ferrara, Italy, ²⁰Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy, ²¹Clinical and Experimental Medicine, Medical Genetics Unit, University of Parma, Parma, Italy, ²²Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy, ²³Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany, ²⁴Internal Medicine III, Jena University Hospital, Jena, Germany, ²⁵Vasculitis Clinic, Klinikum Bad Bramstedt & University Hospital of Schleswig Holstein, Bad Bramstedt, Germany, ²⁶Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany, ²⁷Internal Medicine, Internal Medicine department, Toulouse University Hospital, Toulouse, France, ²⁸Internal Medicine, Hôpital Bichat, Université Paris-Diderot, Paris, France, ²⁹Internal Medicine 2. Referal center for SLE/APS, Hôpital Pitié-Salpêtrière, AP-HP, UPMC Univ Paris 06 & French National Reference Center For Systemic Lupus and Antiphospholipid Syndrome, Paris, France, ³⁰Internal Medicine, Hospital Saint-Louis, Paris, France, ³¹Internal Medicine, Referral Center for Rare Autoimmune and Systemic Diseases, Hôpital Cochin, AP–HP, Université Paris Descartes, Paris, France, Paris, France, ³²Rheumatology, Oslo University Hospital, Oslo, Norway, ³³Rheumatology, Haugesund Sanitetsforenings Revmatismesykehus, Haugesund, Norway, ³⁴Rheumatology, Amsterdam Rheumatology and immunology Center, Location VU University Medical Center, Amsterdam, Netherlands, ³⁵Rheumatology and Clinical Immunology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands, ³⁶Rheumatology, University Hospital Basel, Basel, Switzerland, ³⁷Internal medicine, University hospital Basel, basel, Switzerland, ³⁸Rheumatology, Centre for Arthritis and Rheumatic Diseases, Dublin Academic Medical Centre, St Vincent's University Hospital, Dublin, Ireland, ³⁹Rheumatology, St. Vincent's University Hospital, Dublin, Ireland, ⁴⁰General Internal Medicine, University Hospitals Gasthuisberg, Leuven, Belgium, ⁴¹Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway, ⁴²Swiss Institute of Bioinformatics, Lausanne, Switzerland, ⁴³Division of Immunology, Infection and Inflammatory Disease, King’s College London, London, United Kingdom, ⁴⁴Genetics, University Medical Hospital Groningen, University of Groningen, Groningen, Netherlands, ⁴⁵Rheumatology, Paris Descartes University, Paris, France, ⁴⁶Medical Genetics, University Medical Centre Utrecht, Utrecht, Netherlands, ⁴⁷NIHR-Leeds Musculoskeletal Biomedical Research Unit, Leeds, United Kingdom, ⁴⁸Autoimmune and Systemic Diseases, Hospital Clínic. University of Barcelona. IDIBAPS, Barcelona, Spain, ⁴⁹Rheumatology, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy, ⁵⁰Penn Vasculitis Center, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, ⁵¹Section of Musculoskeletal Disease, NIHR-Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom, ⁵²Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, University of Cantabria, Santander, Spain

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: genomics and giant cell arteritis, GWAS

Session Information

Date: Sunday, November 13, 2016

Title: Vasculitis - Poster I: Large Vessel Vasculitis and Polymyalgia Rheumatica

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Giant cell arteritis (GCA) is an immune-mediated polygenic disease characterized by inflammatory lesions in medium- and large-sized arteries. The aim of the present study was to perform the first unbiased genome-wide association study (GWAS) of GCA in order to identify the most relevant genetic factors contributing to disease predisposition.

Methods: We obtained genome-wide genotypes of 2,134 cases of GCA and 9,125 unaffected controls from 10 different populations of European ancestry (Spain, UK, North America, Italy, Germany, France, Norway, Netherlands, Switzerland, and Ireland). After imputation and tight quality filters, a total of 1,844,133 single-nucleotide polymorphisms were analyzed by logistic regression under an additive model using sex and ten first principal components as covariates. The inverse variance weighted method under fixed effects was used to meta-analyze the different studies.

Results: Two independent signals within the HLA class II region were strongly associated with GCA: rs9268905 (P = 1.94E-54, OR = 1.79, 95% CI = 1.67-1.93), located between the HLA-DRA and HLA-DRB1 genes, and rs9275592 (P = 1.14E-40, OR = 2.08, 95% CI = 1.87-2.32), located between HLA-DQA1 and HLA-DQA2. Outside the HLA region, different genetic variants of plasminogen (PLG) and prolyl 4-hydroxylase subunit alpha 2 (P4HA2), which encode proteins with relevant roles in vascular remodeling and neoangiogenesis, were associated at the genome-wide level of significance (top hits: PLG rs4252134, P = 1.23E-10, OR = 1.28, 95% CI = 1.19-1.39; and P4HA2 rs128738, P = 4.60E-09, OR = 1.32, 95% CI = 1.20-1.45). Using publicly available functional annotation data, we observed that the associated signals correlated with eQTLs and histone marks specific for cell types and tissues involved in GCA pathology.

Conclusion: Consistent with previously published data, our results confirm the HLA class II as the most relevant genetic region for GCA. Additionally, we have identified PLG and P4HA2 as novel GCA risk loci, highlighting the importance of the angiogenesis processes in the development of this form of large vessel vasculitis.

Disclosure: F. D. Carmona, None; A. Vaglio, None; S. Mackie, None; J. Hernández-Rodríguez, None; P. A. Monach, None; S. Castañeda, None; R. Solans, None; I. C. Morado, None; F. J. Narváez, None; M. Ramentol-Sintas, None; C. T. Pease, None; B. Dasgupta, None; R. Watts, None; N. A. Khalidi, None; C. A. Langford, None; S. R. Ytterberg, None; L. Boiardi, None; L. Beretta, None; M. Govoni, None; G. Emmi, None; F. Bonatti, None; M. A. Cimmino, None; T. Witte, None; T. Neumann, None; J. Holle, None; V. Schönau, None; L. Sailler, None; T. Papo, None; J. Haroche, None; A. Mahr, None; L. Mouthon, None; Ø. Molberg, None; A. P. Diamantopoulos, None; A. E. Voskuyl, None; E. Brouwer, None; T. Daikeler, None; C. Berger, None; E. S. Molloy, None; L. O'Neill, None; D. Blockmans, None; B. A. Lie, None; P. Mclaren, None; T. J. Vyse, None; C. Wijmenga, None; Y. Allanore, None; B. P. C. Koeleman, None; J. H. Barrett, None; M. C. Cid, None; C. Salvarani, None; P. A. Merkel, None; A. W. Morgan, None; M. A. González-Gay, None; J. Martín, None.

To cite this abstract in AMA style:

Carmona FD, Vaglio A, Mackie S, Hernández-Rodríguez J, Monach PA, Castañeda S, Solans R, Morado IC, Narváez FJ, Ramentol-Sintas M, Pease CT, Dasgupta B, Watts R, Khalidi NA, Langford CA, Ytterberg SR, Boiardi L, Beretta L, Govoni M, Emmi G, Bonatti F, Cimmino MA, Witte T, Neumann T, Holle J, Schönau V, Sailler L, Papo T, Haroche J, Mahr A, Mouthon L, Molberg Ø, Diamantopoulos AP, Voskuyl AE, Brouwer E, Daikeler T, Berger C, Molloy ES, O'Neill L, Blockmans D, Lie BA, Mclaren P, Vyse TJ, Wijmenga C, Allanore Y, Koeleman BPC, Barrett JH, Cid MC, Salvarani C, Merkel PA, Morgan AW, González-Gay MA, Martín J. New Insights into the Pathogenesis of Giant Cell Arteritis through a Genome-Wide Association Study [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/new-insights-into-the-pathogenesis-of-giant-cell-arteritis-through-a-genome-wide-association-study/. Accessed .

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