Osteoprotegerin CGA Haplotype Protection Against Cerebrovascular Complications in Anti-CCP Negative Patients with Rheumatoid Arthritis

Fernanda Genre¹, Raquel López-Mejías¹, Mercedes García-Bermúdez², Santos Castañeda³, Carlos González-Juanatey⁴, Javier Llorca⁵, Alfonso Corrales¹, Begoña Ubilla¹, Jose A. Miranda-Filloy⁶, Encarnación Amigo⁶, Trinitario Pina Murcia¹, Carmen Gómez-Vaquero⁷, Luis Rodriguez-Rodriguez⁸, Benjamin Fernández Gutierrez⁸, Alejandro Balsa⁹, Dora Pascual-Salcedo⁹, Francisco Javier López-Longo¹⁰, Patricia Carreira¹¹, Ricardo Blanco¹², Isidoro González-Alvaro¹³, Javier Martin¹⁴ and Miguel A González-Gay¹, ¹Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Santander, Spain, ²Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain, ³Rheumatology, Hospital Universitario de La Princesa, IISP, Madrid, Spain, ⁴Hospital Universitario Lucus Augusti. Cardiology Division, Lugo, Spain, ⁵Department of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, and CIBER Epidemiología y Salud Pública (CIBERESP), IDIVAL, Santander, Spain, ⁶Hospital Universitario Lucus Augusti, Rheumatology Division, Lugo, Spain, ⁷Rheumatology Service, Hospital Universitari de Bellvitge - IDIBELL, Barcelona, Spain, ⁸Hospital Clínico San Carlos, Department of Rheumatology, Madrid, Spain, ⁹Hospital Universitario La Paz, Department of Rheumatology, Madrid, Spain, ¹⁰Hospital General Universitario Gregorio Marañón, Department of Rheumatology, Madrid, Spain, ¹¹Hospital Universitario 12 de Octubre, Department of Rheumatology, Madrid, Spain, ¹²Hospital Marques de Valdecilla, Santander, Spain, ¹³Rheumatology, Hospital Universitario de La Princesa. IIS La Princesa, Madrid, Spain, ¹⁴Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Armilla (Granada), Spain

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Cardiovascular disease, osteoprotegerin, polymorphism and rheumatoid arthritis (RA)

Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Rheumatoid arthritis is an inflammatory disease with a high incidence of cardiovascular disease due to accelerated atherosclerosis. Osteoprotegerin (OPG) has been associated with an increased risk of atherosclerotic disease in the general population. Several polymorphisms in the OPG gene with functional effects on cardiovascular disease in non-rheumatic individuals have been described. Therefore, we aimed to analyze the effect of three of these functional OPG polymorphisms on the risk of cardiovascular disease in a large and well-characterized cohort of Spanish patients with rheumatoid arthritis.

Methods: Three OPG gene variants (rs3134063, rs2073618 and rs3134069) were genotyped by TaqMan assays in 2,027 Spanish patients with rheumatoid arthritis. All the patients fulfilled the 1987 American College of Rheumatology (ACR) and also the 2010 classification criteria for RA. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing was positive in 997 out of the 1,714 tested. Also, 18.3% of the whole series had experienced cardiovascular events, including 5.4% with cerebrovascular accidents. The relationship between OPG variants and cardiovascular events was assessed using Cox regression.

Results: No association between OPG gene variants and cardiovascular disease was observed in the whole group of rheumatoid arthritis patients or in anti-CCP positive patients. Nevertheless, a protective effect of CGA haplotype on the risk of cardiovascular disease in general, and specifically in the risk of cerebrovascular complications after adjusting for sex, age at disease diagnosis and traditional cardiovascular risk factors was disclosed in anti-CCP negative patients (HR=0.54; 95%CI: 0.31-0.95; p=0.032 and HR=0.17; 95%CI: 0.04-0.78; p=0.022, respectively). These results were in accordance with a reduced risk of developing cerebrovascular complications observed in those anti-CCP negative patients who carried the OPG rs2073618 GG genotype after adjusting for potential confounder factors (HR=0.17; 95% CI: 0.03-0.89; p=0.035).

Conclusion: Our results indicate a protective effect of the OPG CGA haplotype on cardiovascular risk, mainly due to a protective effect against cerebrovascular events in anti-CCP negative rheumatoid arthritis patients.

This study was supported by European Union FEDER funds and “Fondo de Investigación Sanitaria” (grants PI06/0024, PS09/00748 and PI12/00060) (Spain). This work was also partially supported by RETICS Programs RD12/0009 (RIER) from “Instituto de Salud Carlos III” (ISCIII) (Spain), and in part by grants from the European IMI BTCure Program. FG and BU are supported by funds from the RETICS Program (RIER) (RD12/0009/0013). RLM is a recipient of a Sara Borrell postdoctoral fellowship from the “Instituto de Salud Carlos III” at the Spanish Ministry of Health (Spain) (CD12/00425).

Disclosure:

F. Genre,
None;

R. López-Mejías,
None;

M. García-Bermúdez,
None;

S. Castañeda,
None;

C. González-Juanatey,
None;

J. Llorca,
None;

A. Corrales,
None;

B. Ubilla,
None;

J. A. Miranda-Filloy,
None;

E. Amigo,
None;

T. Pina Murcia,
None;

C. Gómez-Vaquero,
None;

L. Rodriguez-Rodriguez,
None;

B. Fernández Gutierrez,
None;

A. Balsa,
None;

D. Pascual-Salcedo,
None;

F. J. López-Longo,
None;

P. Carreira,
None;

R. Blanco,
None;

I. González-Alvaro,
None;

J. Martin,
None;

M. A. González-Gay,
None.

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