ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 892

The Functional PTPN22 Variant R620W Is Strongly Associated With Giant Cell Artetitis Predisposition

F. David Carmona1, Sarah L. Mackie2, Aurora Serrano3, Ana Marquez4, Roser Solans5, Jose A. Miranda-Filloy6, Jose Hernández-Rodríguez7, Maria C. Cid8, Santos Castañeda9, Inmaculada C. Morado10, Javier Narvaez11, Ricardo Blanco12, Bernardo Sopeña13, M. Jesus García-Villanueva14, Jordi Monfort15, Norberto Ortego-Centeno16, Ainhoa Unzurrunzaga17, Begoña Marí-Alfonso18, Julio Sánchez-Martín19, Eugenio de Miguel20, Cesar Magro21, Enrique Raya22, Niko Braun23, Joerg Latus24, Øyvind Molberg25, Benedicte A. Lie26, Frank Moosig27, Torsten Witte28, Ann W. Morgan2, Miguel A. González-Gay29 and Javier Martin3, 1Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Armilla (Granada), Spain, 2NIHR-Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom, 3Instituto de Parasitologia y Biomedicina Lopez-Neyra (IPBLN-CSIC), Granada, Spain, 4Instituto de Parasitología y Biomedicina 'López-Neyra' (IPBLN-CSIC), Granada, Spain, 5Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain, 6Rheumatology, Division of Rheumatology, Hospital Lucus Augusti, Lugo, Spain, 7Hospital Clínic. University of Barcelona. IDIBAPS, Barcelona, Spain, 8Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 9Rheumatology, Hospital Universitario de La Princesa, IIS Princesa, Madrid, Spain, 10Rheumatology, Hospital Clínico San Carlos, Madrid, Spain, 11Rheumatology, Hospital Universitario de Bellvitge, Barcelona, Spain, 12Rheumatology, Hospital Universitario Marqués de Valdecilla. IFIMAV. Santander. Spain, Santander, Spain, 13Thrombosis and Vasculitis Unit-Internal Medicine, Complejo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain, 14Rheumatology, Hospital Ramón y Cajal, Madrid, Spain, 15Reumatologia, Hospital del Mar, Barcelona, Spain, 16Systemic Autoimmune Diseases Unit, Hospital Clínico San Cecilio, Granada, Spain, 17Internal Medicine, Hospital de Galdakano, Vizcaya, Spain, 18Internal Medicine, Corporació Sanitaria Parc Taulí, Instituto Universitario Parc Taulí, UAB, Sabadell, Spain, 19Rheumatology,, Hospital Universitario 12 de Octubre, Madrid, Spain, 20Rheumatology, University Hospital La Paz - IdiPaz, Madrid, Spain, 21Rheumatology, Hospital Clínico San Cecilio, Granada, Spain, 22Rheumatology, University Hospital San Cecilio, Granada, Spain, 23Department of Internal Medicine, Division of Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany, 24Internal Medicine, Division of Nephrology, Robert-Bosch-Hospital, Stuttgart, Germany, 25Oslo University Hospital, Oslo, Norway, 26Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway, 27Department of Clinical Immunology and Rheumatology, University of Luebeck, Bad Bramstedt, Germany, 28Clinical Immunology and Rheumatology, Medical University Hannover, Hanover, Germany, 29Rheumatology, Hospital Universitario Marqués de Valdecilla. IDIVAL. Santander. Spain, Santander, Spain

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Vasculitis I

Session Type: Abstract Submissions (ACR)

Background/Purpose:

The PTPN22/CSK signaling represents one of the common susceptibility pathways in autoimmunity. Considering that the genetic basis of giant cell arteritis (GCA), an autoimmune vasculitis of complex etiology, remains poorly understood, we decided to analyze whether variations within the PTPN22 and CSK genes are associated with GCA predisposition and/or severity in a well-powered case/control cohort.

Methods: The study comprised a discovery cohort from Spanish Caucasian ancestry of 623 biopsy-proven GCA cases and 1,729 unaffected controls, and a replication Caucasian cohort from three different European countries (UK, Norway and Germany) consisting of 288 biopsy-proven GCA patients and 6,407 unaffected controls. Two non-synonymous functional PTPN22 polymorphisms (rs24746601/R620W and rs33996649/R263Q) and two additional CSK variants that have been associated with systemic sclerosis (rs1378942) and systemic lupus erythematosus (rs34933034) were genotyped using TaqMan© probes. The statistical analyses were performed with Plink.

Results: A clear association of the PTN22 classical polymorphism rs24746601/R620W with GCA was observed in the discovery cohort, which was maintained after FDR correction for multiple testing (corrected P=1.06E-04, OR=1.62, CI 95%=1.29-2.04). This association was further confirmed in the replication set of independent European cohorts, whose meta-analysis also reached statistical significance (PMH=0.015, OR=1.38, CI 95%=1.07-1.77). A strong association signal was observed when the four European cohorts were combined (PMH=2.00E-06, OR=1.51, CI 95%=1.28-1.79). The comparison between the analysed clinical phenotypes (i.e. polymyalgia rheumatica, visual ischemic manifestations, and irreversible occlusive disease) and the control set also yielded significant P-values for PTPN22 R620W; however, no association was observed when the GCA cases positive and negative for each clinical characteristic were compared, suggesting that this PTPN22 variant is associated with the whole disease. None of the other analyzed polymorphisms showed evidence of association either with the global disease or with the different phenotypes.

Conclusion: Our results clearly indicate that the autoimmune-disease associated PTPN22 polymorphism rs24746601/R620W confers risk to develop GCA.

Disclosure:

F. D. Carmona,
None;

S. L. Mackie,
None;

A. Serrano,
None;

A. Marquez,
None;

R. Solans,
None;

J. A. Miranda-Filloy,
None;

J. Hernández-Rodríguez,
None;

M. C. Cid,
None;

S. Castañeda,
None;

I. C. Morado,
None;

J. Narvaez,
None;

R. Blanco,
None;

B. Sopeña,
None;

M. J. García-Villanueva,
None;

J. Monfort,
None;

N. Ortego-Centeno,
None;

A. Unzurrunzaga,
None;

B. Marí-Alfonso,
None;

J. Sánchez-Martín,
None;

E. de Miguel,
None;

C. Magro,
None;

E. Raya,
None;

N. Braun,
None;

J. Latus,
None;

Molberg,
None;

B. A. Lie,
None;

F. Moosig,
None;

T. Witte,
None;

A. W. Morgan,
None;

M. A. González-Gay,
None;

J. Martin,
None.

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