Steroid hormone-related polymorphisms associate with the development of bone erosions in rheumatoid arthritis and help to predict disease progression: Results from the REPAIR consortium

Here, we assessed whether 41 SNPs within steroid hormone genes associated with erosive disease. The most relevant finding was the rheumatoid factor (RF)-specific effect of the CYP1B1 , CYP2C9 , ESR2 , FcγR3A , and SHBG SNPs to modulate the risk of bone erosions ( P = 0.004, 0.0007, 0.0002, 0.013 and 0.015) that was confirmed through meta-analysis of our data with those from the DREAM registry ( P = 0.000081, 0.0022, 0.00074, 0.0067 and 0.0087, respectively). Mechanistically, we also found a gender-specific correlation of the CYP2C9 rs1799853T/T genotype with serum vitamin D3 levels ( P = 0.00085) and a modest effect on IL1β levels after stimulation of PBMCs or blood with LPS and PHA ( P = 0.0057 and P = 0.0058). An overall haplotype analysis also showed an association of 3 ESR1 haplotypes with a reduced risk of erosive arthritis ( P = 0.009, P = 0.002, and P = 0.002). Furthermore, we observed that the ESR2 , ESR1 and FcγR3A SNPs influenced the immune response after stimulation of PBMCs or macrophages with LPS or Pam3Cys (P = 0.002, 0.0008, 0.0011 and 1.97•10 −7 ). Finally, we found that a model built with steroid hormone-related SNPs significantly improved the prediction of erosive disease in seropositive patients ( P RF+ = 2.46•10 −8 ) whereas no prediction was detected in seronegative patients ( P RF− = 0.36). Although the predictive ability of the model was substantially lower in the replication population ( P RF+ = 0.014), we could confirm that CYP1B1 and CYP2C9 SNPs help to predict erosive disease in seropositive patients. These results are the first to suggest a RF-specific association of steroid hormone-related polymorphisms with erosive disease.