Open Access Open Badges Research article

A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis

Rachel Knevel1*, Diederik PC de Rooy1, Tore Saxne2, Elisabet Lindqvist2, Martha K Leijsma3, Nina A Daha1, Bobby PC Koeleman4, Roula Tsonaka5, Jeanine J Houwing-Duistermaat5, Joris JM Schonkeren1, Rene EM Toes1, Tom WJ Huizinga1, Elisabeth Brouwer3, Anthony G Wilson6 and Annette HM van der Helm-van Mil1

Author Affiliations

1 Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands

2 Department of Rheumatology, Lund University, Lund, Sweden

3 Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

4 Complex Genetics Section, Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands

5 Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands

6 School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, UK

For all author emails, please log on.

Arthritis Research & Therapy 2014, 16:R108  doi:10.1186/ar4558

Published: 7 May 2014



Progression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor Îș B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA.


1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied.


We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (P = 2.35x10−4). This variant was also significant after Bonferroni correction.


These results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.