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

Jose M. Sanchez-Maldonado, Rafael Caliz, Luz Cana, Rob ter Horst, Olivier Bakker, Alfons A. den Broeder, Manuel Martinez-Bueno, Helena Canhao, Ana Rodriguez-Ramos, Carmen B. Lupianez, Maria Jose Soto-Pino, Antonio Garcia, Eva Perez-Pampin, Alfonso Gonzalez-Utrilla, Alejandro L. Escudero, Juana Segura-Catena, Romana T. Netea-Maier, Miguel Angel Ferrer, Eduardo Collantes-Estevez, Miguel Angel Lopez NevotYang Li, Manuel Jurado, Joao E. Fonseca, Mihai G. Netea, Marieke J. H. Coenen, Juan Sainz*

*Bijbehorende auteur voor dit werk

    OnderzoeksoutputAcademicpeer review

    2 Citaten (Scopus)
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    Samenvatting

    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, FcyR3A, 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 rs(1799853T/T) genotype with serum vitamin D3 levels (P= 0.00085) and a modest effect on IL1 beta 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 FcyR3A SNPs influenced the immune response after stimulation of PBMCs or macrophages with LPS or Pam3Cys (P = 0.002, 0.0008, 0.0011 and 1.974,10(-7)). Finally, we found that a model built with steroid hormone-related SNPs significantly improved the prediction of erosive disease in seropositive patients (PRF- = 2.46.10(-8)) whereas no prediction was detected in seronegative patients (PRF- = 0.36). Although the predictive ability of the model was substantially lower in the replication population (PRF+ = 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.

    Originele taal-2English
    Artikelnummer14812
    Aantal pagina's16
    TijdschriftScientific Reports
    Volume9
    DOI's
    StatusPublished - 15-okt-2019

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