Association between RANK, RANKL and OPG polymorphisms with ACPA and erosions in rheumatoid arthritis: results from a meta-analysis involving three French cohorts.

Objectives: The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in the pathogenesis of bone erosions in rheumatoid arthritis (RA). The aim of this study was to test the association between 11 single-nucleotide polymorphisms (SNPs) located on RANK, RANKL and OPG genes and anticitrullinated peptide antibody (ACPA) presence or erosions in RA.

Patients: This work was performed on three independent samples of French patients with RA: the Etude de Suivi des PolyArthrites Indifférenciées Récentes (ESPOIR) (n=632), Rangueil Midi-Pyrénées (RMP) (n=249) and French Rheumatoid Arthritis Genetic Consortium (FRAGC) (n=590) cohorts. Genotyping: the genotyping of 11 SNPs located on RANK, RANKL and OPG were performed by PCR.

Statistical Analyses: The association between the genotypes with ACPA or erosions was first tested in the ESPOIR cohort using a χ(2) test and, in the case of significant association, replicated in the RMP and FRACG cohorts. A meta-analysis on the three cohorts was performed using the Mantel-Haenszel method.

Results: One SNP on RANK (rs8086340) and three SNPs on RANKL (rs7984870, rs7325635, rs1054016) were significantly associated with ACPA presence, while one SNP on OPG (rs2073618) and one SNP on RANKL (rs7325635) were significantly associated with erosions in the ESPOIR cohort. Following meta-analysis performed on the three samples, the SNP on RANK and the GGG haplotype of the three SNPs located on RANKL were both significantly associated with ACPA presence, while only the SNP on OPG remained significantly associated with erosions.

Conclusions: This study identified one SNP located on RANK, one haplotype on RANKL associated with ACPA presence, and one SNP located on OPG associated with erosions in three different samples of French patients with RA.