A Candidate Gene Approach Identifies IL33 as a Novel Genetic Risk Factor for GCA

Ana Márquez¹, Roser Solans², José Hernández-Rodríguez³, Maria C. Cid⁴, Santos Castañeda⁵, Marc Ramentol⁶, Luis Rodriguez-Rodriguez⁷, Javier Narváez⁸, Ricardo Blanco⁹, Norberto Ortego-Centeno¹⁰, Øyvind Palm¹¹, Andreas P. Diamantopoulos¹², Niko Braun¹³, Frank Moosig¹⁴, Torsten Witte¹⁵, Lorenzo Beretta¹⁶, Claudio Lunardi¹⁷, Marco A. Cimmino¹⁸, Augusto Vaglio¹⁹, Carlo Salvarani²⁰, Miguel A. Gonzalez-Gay²¹ and Javier Martin²², ¹Instituto de Parasitologia y Biomedicina López-Neyra (IPBLN-CSIC) and Systemic Autoimmune Diseases Unit, Hospital Clínico San Cecilio, Granada, Spain, ²Autoimmune Systemic Diseases Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain, ³Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, ⁴Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036- Barcelona, Spain, ⁵Department of Rheumatology, Hospital de la Princesa, IIS-Princesa, Madrid, Spain, ⁶Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain, ⁷Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain, ⁸Rheumatology, Hospital Universitario de Bellvitge. Barcelona. Spain, Barcelona, Spain, ⁹Hospital Marques de Valdecilla, Santander, Spain, ¹⁰Systemic Autoimmune Diseases Unit, Hospital Clínico San Cecilio, Granada, Spain, ¹¹Department of Rheumatology, Oslo University Hospital and University of Oslo, Oslo, Norway, ¹²Rheumatology, Hospital of Southern Norway Trust, Kristiansand, Norway, ¹³Department of Internal Medicine, Division of Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany, ¹⁴Department of Clinical Immunology and Rheumatology, University of Luebeck, Bad Bramstedt, Germany, ¹⁵Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany, ¹⁶Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, ¹⁷Department of Medicine, Università degli Studi di Verona, Verona, Italy, ¹⁸Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genoa, Italy, ¹⁹Unit of Nephrology, University Hospital of Parma, Parma, Italy, ²⁰Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera ASMN, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy, ²¹Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain, ²²Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Armilla (Granada), Spain

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: giant cell arteritis, polymorphism and temporal arteritis

Session Information

Session Title: Vasculitis

Session Type: Abstract Submissions (ACR)

Background/Purpose: IL-33, through binding to its receptor ST2 (suppression of tumorigenicity 2), encoded by the interleukin 1 receptor-like 1 (IL1RL1) gene, activates mast cells and Th2 lymphocytes. Additionally, IL-33 acts as an activator of endothelial cells promoting angiogenesis and vascular permeability. Different studies have supported a pathogenic role of IL-33 axis in autoimmunity. Interestingly, an increased expression of this cytokine and its receptor has been detected in the inflamed arteries of GCA patients, mainly in endothelial cells of newly formed vessels, thus suggesting a possible role of IL-33 in the angiogenesis-dependent inflammation in GCA. 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 case/control sets (Spanish cohort: 894 cases and 2,047 controls, German cohort: 103 cases and 444 controls, Italian cohort: 255 cases and 1,141 controls, and Norwegian cohort: 111 cases and 276 controls) 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 autoimmunity, 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.

Conclusion: Our results clearly evidenced the implication of the IL33 locus in the genetic network underlying GCA. This study, together with previous findings, supports an important role of this cytokine in the inflammatory process occurring in GCA.

Disclosure:

A. Márquez,
None;

R. Solans,
None;

J. Hernández-Rodríguez,
None;

M. C. Cid,
None;

S. Castañeda,
None;

M. Ramentol,
None;

L. Rodriguez-Rodriguez,
None;

J. Narváez,
None;

R. Blanco,
None;

N. Ortego-Centeno,
None;

Palm,
None;

A. P. Diamantopoulos,
None;

N. Braun,
None;

F. Moosig,
None;

T. Witte,
None;

L. Beretta,
None;

C. Lunardi,
None;

M. A. Cimmino,
None;

A. Vaglio,
None;

C. Salvarani,
None;

M. A. Gonzalez-Gay,
None;

J. Martin,
None.

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