A Candidate Gene Approach Identifies an IL33 Genetic Variant as a Novel Genetic Risk Factor for GCA Ana Ma ´ rquez 1,2 *, Roser Solans 3 , Jose ´ Herna ´ndez-Rodrı´guez 4 , Maria C. Cid 4 , Santos Castan ˜ eda 5 , Marc Ramentol 3 , Luis Rodriguez-Rodriguez 6 , Javier Narva ´ez 7 , Ricardo Blanco 8 , Norberto Ortego-Centeno 2 , Spanish GCA Consortium ` , Øyvind Palm 9 , Andreas P. Diamantopoulos 10 , Niko Braun 11 , Frank Moosig 12 , Torsten Witte 13 , Lorenzo Beretta 14 , Claudio Lunardi 15 , Marco A. Cimmino 16 , Augusto Vaglio 17 , Carlo Salvarani 18 , Miguel A. Gonza ´ lez-Gay 8" , Javier Martı´n 1" 1 Instituto de Parasitologı ´a y Biomedicina Lo ´ pez-Neyra, CSIC, Granada, Spain, 2 Systemic Autoimmune Diseases Unit, Hospital Clı ´nico San Cecilio, Granada, Spain, 3 Department of Internal Medicine, Hospital Vall d’Hebron, Barcelona, Spain, 4 Vasculitis Research Unit, Department of Autoimmune and Systemic Diseases, Hospital Clinic, University of Barcelona, Centre de Recerca Biome `dica Cellex (IDIBAPS), Barcelona, Spain, 5 Department of Rheumatology, Hospital de la Princesa, IIS-Princesa, Madrid, Spain, 6 Department of Rheumatology, Hospital Clı ´nico San Carlos, Madrid, Spain, 7 Department of Rheumatology, Hospital Universitario de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain, 8 Department of Rheumatology, Hospital Universitario Marque ´s de Valdecilla, IFIMAV, Santander, Spain, 9 Department of Rheumatology, Oslo University Hospital Rikshospitalet, Oslo, Norway, 10 Department of Rheumatology, Hospital of Southern Norway Trust, Kristiansand, Norway, 11 Department of Internal Medicine, Division of Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany, 12 Department of Clinical Immunology and Rheumatology, University of Luebeck, Bad Bramstedt, Germany, 13 Hannover Medical School, Hannover, Germany, 14 Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, 15 Department of Medicine, Universita ` degli Studi di Verona, Verona, Italy, 16 Department of Internal Medicine, Academic Unit of Clinical Rheumatology, University of Genova, Genova, Italy, 17 Department of Clinical Medicine, Nephrology and Health Sciences, University Hospital of Parma, Parma, Italy, 18 Unita ` Operativa di Reumatologia, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy Abstract Introduction: Increased expression of IL-33 and its receptor ST2, encoded by the IL1RL1 gene, has been detected in the inflamed arteries of giant cell arteritis (GCA) patients. The aim of the present study was to investigate for the first time the potential influence of the IL33 and IL1RL1 loci on GCA predisposition. Methods: A total of 1,363 biopsy-proven GCA patients and 3,908 healthy controls from four European cohorts (Spain, Italy, Germany and Norway) were combined in a meta-analysis. Six genetic variants: rs3939286, rs7025417 and rs7044343, within the IL33 gene, and rs2058660, rs2310173 and rs13015714, within the IL1RL1 gene, previously associated with immune- related diseases, were genotyped using predesigned TaqMan assays. Results: A consistent association between the rs7025417 polymorphism and GCA was evident in the overall meta-analysis, under both allele (P MH = 0.041, OR = 0.88, CI 95% 0.78–0.99) and recessive (P MH = 3.40E-03, OR = 0.53, CI 95% 0.35–0.80) models. No statistically significant differences between allele or genotype frequencies for the other IL33 and IL1RL1 genetic variants were detected in this pooled analysis. Conclusions: Our results clearly evidenced the implication of the IL33 rs7025417 polymorphism in the genetic network underlying GCA. Citation: Ma ´ rquez A, Solans R, Herna ´ndez-Rodrı ´guez J, Cid MC, Castan ˜ eda S, et al. (2014) A Candidate Gene Approach Identifies an IL33 Genetic Variant as a Novel Genetic Risk Factor for GCA. PLoS ONE 9(11): e113476. doi:10.1371/journal.pone.0113476 Editor: Paolo Peterlongo, IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Italy Received July 28, 2014; Accepted October 24, 2014; Published November 19, 2014 Copyright: ß 2014 Ma ´rquez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This study was partially supported by RETICS Program RD08/0075/0011 (RIER) from ‘Instituto de Salud Carlos III’ (ISCIII) and by Junta de Andalucı ´a, grupo CTS-180. MCC and JH-R were granted by SAF 11/30073. TW was granted by DFG WI 1031/6.1. The sponsors had no role in the design of the study, in the collection, analysis and interpretation of data or in the preparation, review or approval of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: anamaort@ipb.csic.es " MAGG and JM share senior authorship on this work. ` Membership of the Spanish GCA Consortium is provided in File S1. PLOS ONE | www.plosone.org 1 November 2014 | Volume 9 | Issue 11 | e113476