Osteoprotegerin CGA haplotype protection against cerebrovascular complications in anti-CCP negative patients with rheumatoid arthritis

PLoS One. 2014 Sep 3;9(9):e106823. doi: 10.1371/journal.pone.0106823. eCollection 2014.

Abstract

Introduction: 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).

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.

Publication types

  • Clinical Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid* / blood
  • Arthritis, Rheumatoid* / complications
  • Arthritis, Rheumatoid* / genetics
  • Autoantibodies / blood*
  • Cerebrovascular Disorders* / blood
  • Cerebrovascular Disorders* / etiology
  • Cerebrovascular Disorders* / genetics
  • Female
  • Haplotypes*
  • Humans
  • Male
  • Middle Aged
  • Osteoprotegerin / genetics*
  • Peptides, Cyclic / blood
  • Polymorphism, Single Nucleotide*
  • Spain

Substances

  • Autoantibodies
  • Osteoprotegerin
  • Peptides, Cyclic
  • TNFRSF11B protein, human
  • cyclic citrullinated peptide

Grants and funding

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). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.