title: Osteoprotegerin CGA haplotype protection against cerebrovascular complications in anti-CCP negative patients with rheumatoid arthritis.
abstract: BACKGROUND
  Rheumatoid arthritis is an inflammatory disease with high incidence of cardiovascular disease due to accelerated atherosclerosis. Osteoprotegerin (OPG) has been associated with 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 2027 Spanish patients with rheumatoid arthritis. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing was positive in 997 of 1714 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Santander, Spain.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Genre
authors.affiliation: Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Santander, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: López-Mejías
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: García-Bermúdez
authors.affiliation: Department of Rheumatology, Hospital Universitario la Princesa, IIS-Princesa, Madrid, Spain.
authors.forename: Santos
authors.initials: S
authors.lastname: Castañeda
authors.affiliation: Cardiology Division, Hospital Universitario Lucus Augusti, Lugo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: González-Juanatey
authors.affiliation: Department of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, and CIBER Epidemiología y Salud Pública (CIBERESP), IDIVAL, Santander, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Llorca
authors.affiliation: Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Santander, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Corrales
authors.affiliation: Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Santander, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Ubilla
authors.affiliation: Division of Rheumatology, Hospital Universitario Lucus Augusti, Lugo, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Miranda-Filloy
authors.affiliation: Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Santander, Spain.
authors.forename: Trinitario
authors.initials: T
authors.lastname: Pina
authors.affiliation: Department of Rheumatology, Hospital Universitario Bellvitge, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gómez-Vaquero
authors.affiliation: Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rodríguez-Rodríguez
authors.affiliation: Department of Rheumatology, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Fernández-Gutiérrez
authors.affiliation: Department of Rheumatology, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.affiliation: Department of Rheumatology, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Dora
authors.initials: D
authors.lastname: Pascual-Salcedo
authors.affiliation: Department of Rheumatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López-Longo
authors.affiliation: Department of Rheumatology, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Carreira
authors.affiliation: Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Santander, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Blanco
authors.affiliation: Department of Rheumatology, Hospital Universitario la Princesa, IIS-Princesa, Madrid, Spain.
authors.forename: Isidoro
authors.initials: I
authors.lastname: González-Álvaro
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martín
authors.affiliation: Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IDIVAL, Santander, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: González-Gay
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000150:complications / Q000235:genetics; D001323:Autoantibodies / Q000097:blood*; D002561:Cerebrovascular Disorders / Q000097:blood / Q000209:etiology / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D053244:Osteoprotegerin / Q000235:genetics*; D010456:Peptides, Cyclic / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D013030:Spain
chemical_list: D001323:Autoantibodies; D053244:Osteoprotegerin; D010456:Peptides, Cyclic; C506030:TNFRSF11B protein, human; C487763:cyclic citrullinated peptide