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

• Published in: Scientific reports Vol. 9; no. 1; pp. 14812 - 16
• Main Authors: Sánchez-Maldonado, Jose M., 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.10.2019; Nature Publishing Group
• Subjects: 13; 13/31; 13/56; 45; 45/22; 45/77; 59; 692/4023/1670/498; 692/53/2422; 82; 82/58; 96/21; Adult; Aged; Arthritis; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - complications; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Bone Diseases - diagnosis; Bone Diseases - genetics; Bone Diseases - immunology; Cytochrome P-450 CYP1B1 - genetics; Cytochrome P-450 CYP1B1 - metabolism; Cytochrome P-450 CYP2C9 - genetics; Cytochrome P-450 CYP2C9 - metabolism; Disease Progression; ESR1 protein; Female; Gender; Gonadal Steroid Hormones - immunology; Gonadal Steroid Hormones - metabolism; Haplotypes; Humanities and Social Sciences; Humans; Immune response; Interleukin 1; Lipopolysaccharides; Macrophages; Male; Menopause; Middle Aged; multidisciplinary; Polymorphism, Single Nucleotide; Predictive Value of Tests; Prognosis; Retrospective Studies; Rheumatoid arthritis; Rheumatoid factor; Rheumatoid Factor - blood; Rheumatoid Factor - immunology; Science; Science (multidisciplinary); Single-nucleotide polymorphism; Steroids; Vitamin D; Vitamin D3
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-51255-0

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.