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Abstract Number: 747

Systemic Sclerosis Patients with Antitopoisomerase Antibodies Showed Significant Association with CCR6 Polymorphisms

Javier Martin1, Eguzkine Ochoa2, Jose Ezequiel Martin1, Shervin Assassi3, Lorenzo Beretta4, Patricia Carreira5, Carmen Pilar Simeon6, Eugénie Koumakis7, Philippe Dieude8, Yannick Allanore9, Francisco J. García-Hernández10, Gerard Espinosa11, Ivan Castellvi Barranco12, Luis Trapiella13, Luis Rodriguez Rodriguez14, Miguel A González-Gay15, María-Victoria Egurbide16, Luis Saez17, José Luis Callejas18, JA Vargas-Hitos19, Nicolas Hunzelmann20, Gabriela Riemekasten21, Torsten Witte22, Jörg HW Distler23, Alexander Kreuter24, Claudio Lunardi25, Alessandro Santaniello26, Filemon K. Tan3, Frank C. Arnett3, Paul Shiels27, Ariane L. Herrick28, Jane Worthington29, Madelon C. Vonk30, Bobby P.C. Koeleman31, T.R.D.J. Radstake32 and Maureen Mayes33, 1Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Armilla (Granada), Spain, 2Immunology, Instituto de Parasitología y Biomedicina Lopez Neyra (IPBLN-CSIC), Granada, Spain, 3Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, 4Via Francesco Sforza 28, Ospedale Maggiore Policlinico, Milano, Italy, 5Hospital Universitario 12 de Octubre, Department of Rheumatology, Madrid, Spain, 6Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain, 7Rheumatology A department, Cochin Hospital, Paris Descartes University, Rheumatology A department, Cochin Hospital, Paris, France, 8Rhumatologie, Hopital Bichat Claude Bernard, Paris, France, 9Department of Rheumatology, University Paris Descartes and Cochin Hospital, Paris, France, 10Internal Medicine, Hospital Virgen del Rocío, Sevilla, Spain, 11Department of Autoimmune Diseases, Hospital Clínic, Barcelona, Barcelona, Spain, 12Hosp. De Sta. Creu i S. Pau, Vilafranca del Pened, Spain, 13Department of Internal Medicine,, Hospital Universitario Central de Asturias, Asturias, Spain, 14Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain, 15Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Santander, Spain, 16Autoimmune Disease Research Unit, Service of Internal Medicine,, Hospital de Cruces, UPV/EHU, Barakaldo, Spain, Barakaldo, Spain, 17Unidad de Enfermedades Autoinmunes, Servicio de Medicina Interna, Hospital Miguel Servet, Zaragoza, Spain, 18Internal Medicine, Hospital Clínico San Cecilio, Granada, Spain, 19Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain, 20Department of Dermatology, University of Cologne, Cologne, Germany, 21Charité University Hospital and German Rheumatism Research Centre, a Leibniz Institute, Berlin, Germany, 22Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany, 23Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 24Department of Dermatology, Venereology, and Allergologie, HELIOS St. Elisabeth Hospital, Oberhausen, Germany, 25Department of Medicine, Università degli Studi di Verona, Verona, Italy, 26Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, 27University of Glasgow, Glasgow, United Kingdom, 28Musculoskeletal Research Group, School of Translational Medicine, Manchester Academic Health Science Centre, Salford Royal Hospital, University of Manchester., Salford, United Kingdom, 29Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester, United Kingdom, 30Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 31Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands, 32Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, 33Internal Medicine/Rheumatology, University of TX Health Science Center -Houston, Houston, TX

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Genetic Biomarkers, meta-analysis, severity and systemic sclerosis

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Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic sclerosis (SSc), also known as scleroderma, is an inflammatory autoimmune disease characterized by fibrosis of the skin and internal organs, vascular damage and altered immune responses with autoantibody production (especially anticentromere (ACA) and antitopoisomerase I (ATA)). As a complex disease, SSc, is caused by a combination of genetic and environmental factors. In recent years, the number of new susceptibility loci associated with SSc has remarkably grown due to genome-wide association studies (GWAS).  Nevertheless, the current knowledge of the influence of SSc risk loci in the clinical sub-phenoytpes is limited and one of the main reasons is the low sample size in sub-phenotypes that triggers a lower statistical power. In this regard, ATA+ SSc patients have been recently associated with CCR6 gene variants and the main limitations of the study was the low sample size due to the low frequency of ATA among SSc patients (around 20%). Thus, in order to confirm the CCR6 association with ATA+ SSc, we performed an independent replication study in populations of European ancestry and a meta-analysis with the previous data published.

Methods: We selected for replication SNP rs3093024, in high linkage disequilibrium with the SNPs previously associated with ATA+ SSc, rs3093023 (r2=1) and rs10946216 (r2=0.96). We designed a replication study with two phases: In phase I, we analyzed 454 ATA+ SSc cases and 4,867 controls from available GWAS genotyped platform by Radstake et al. and in phase II, 446 ATA+ SSc cases and 2,998 controls from five additional European cohorts were genotyped using TaqMan SNP® genotyping assay. Approval of local ethical committees and informed written consent was obtained for all participants. The meta-analysis of our study with the previous one included 1,548 ATA+ SSc cases and 14,777 controls and reached statistical power of the analysis to 99% (OR 1.16, MAF 0.43, at the 5% significant level). 

Results: Results obtained in meta-analysis showed significant association between SNP rs3093024 and ATA+ SSc patients (P= 1.0 x 10-4, OR=1.16) (Table 1). Thus we confirm the association previously observed between CCR6 and ATA+ SSc patients harnessing the largest cohort of patients. The relevance of CCR6 gene lies in its function as specific marker for Th17 cells. These cells are characterized by the production of interleukin-17 (IL- 17) which has been found to be increased in patients with SSc. Besides serum levels of IL-17 and ATA presence have been both correlated with disease severity. Interestingly, CCR6 expression levels and IL-17 levels showed correlation with a CCR6 functional variant which was in high linkage disequilibrium with SNP rs3093024 in rheumatoid arthritis patients.

Conclusion: Taken all together, our findings suggest that the presence of the risk variant of rs3093024 in CCR6 gene may acts as a marker of severity in SSc patients.


Disclosure:

J. Martin,
None;

E. Ochoa,
None;

J. E. Martin,
None;

S. Assassi,
None;

L. Beretta,
None;

P. Carreira,
None;

C. P. Simeon,
None;

E. Koumakis,
None;

P. Dieude,
None;

Y. Allanore,
None;

F. J. García-Hernández,
None;

G. Espinosa,
None;

I. Castellvi Barranco,
None;

L. Trapiella,
None;

L. Rodriguez Rodriguez,
None;

M. A. González-Gay,
None;

M. V. Egurbide,
None;

L. Saez,
None;

J. L. Callejas,
None;

J. Vargas-Hitos,
None;

N. Hunzelmann,
None;

G. Riemekasten,
None;

T. Witte,
None;

J. H. Distler,
None;

A. Kreuter,
None;

C. Lunardi,
None;

A. Santaniello,
None;

F. K. Tan,
None;

F. C. Arnett,
None;

P. Shiels,
None;

A. L. Herrick,
None;

J. Worthington,
None;

M. C. Vonk,
None;

B. P. C. Koeleman,
None;

T. R. D. J. Radstake,
None;

M. Mayes,
None.

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