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

• Autor(a) principal: Sánchez-Maldonado, Jose M.
• Data de Publicação: 2019
• Outros Autores: Cáliz, Rafael, Canet, Luz, Horst, Rob ter, Bakker, Olivier, den Broeder, Alfons A., Martínez-Bueno, Manuel, Canhão, Helena, Rodríguez-Ramos, Ana, Lupiañez, Carmen B., Soto-Pino, María José, García, Antonio, Pérez-Pampin, Eva, González-Utrilla, Alfonso, Escudero, Alejandro, Segura-Catena, Juana, Netea-Maier, Romana T., Ferrer, Miguel Ángel, Collantes-Estevez, Eduardo, López Nevot, Miguel Ángel, Li, Yang, Jurado, Manuel, Fonseca, João E., Netea, Mihai G., Coenen, Marieke J.H., Sainz, Juan
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: https://doi.org/10.1038/s41598-019-51255-0
• topic: General

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 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.