Sanchez-Maldonado, Jose MCaliz, RafaelCanet, LuzHorst, Rob TerBakker, Olivierden Broeder, Alfons AMartinez-Bueno, ManuelCanhão, HelenaRodriguez-Ramos, AnaLupiañez, Carmen BSoto-Pino, Maria JoseGarcia, AntonioPerez-Pampin, EvaGonzalez-Utrilla, AlfonsoEscudero, AlejandroSegura-Catena, JuanaNetea-Maier, Romana TFerrer, Miguel AngelCollantes-Estevez, EduardoLopez Nevot, Miguel AngelLi, YangJurado, ManuelFonseca, João ENetea, Mihai GCoenen, Marieke J HSainz, Juan2023-02-082023-02-082019-09-28Sánchez-Maldonado JM, Cáliz R, Canet L, Horst RT, Bakker O, den Broeder AA, et al. 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. Sci Rep. 2019 Oct 15;9(1):14812http://hdl.handle.net/10668/14834Here, 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 CYP2C9rs1799853T/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 (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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Polymorphism, single nucleotidePredictive value of testsPrognosisRetrospective studiesRheumatoid factorAdultAgedArthritis, rheumatoidBone diseasesCytochrome P-450 CYP1B1Cytochrome P-450 CYP2C9Disease progressionFemaleGonadal steroid hormonesHaplotypesHumansMaleMiddle agedresearch article31616008open accessArtritis reumatoideCitocromo P-450 CYP1B1Citocromo P-450 CYP2C9Enfermedades óseasHaplotiposHormonas esteroides gonadalesProgresión de la enfermedad10.1038/s41598-019-51255-02045-2322PMC6794376https://www.nature.com/articles/s41598-019-51255-0.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794376/pdf