CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women

Abstract

IntroductionRheumatoid arthritis (RA) is characterized by decreased androgen levels, which was the first hormonal abnormality described. Several studies indicated that steroidogenesis is directed towards endogenous glucocorticoids at the expense of androgens. The decisive step governing androgen synthesis is the 17,20-lyase activity of the CYP17A1 gene-encoded enzyme cytochrome P450 17A1. Here, we focused on the role in RA of the critical cofactor for 17,20-lyase activity, cytochrome b5, encoded by the CYB5A gene.MethodsData sets of two genome wide RA association studies (GWAS) were screened for single nucleotide polymorphisms (SNP) in the CYB5A gene. Candidate SNPs in CYB5A were studied in a case–control study population of Slovakia. Expression analyses were done in synovial fibroblasts from RA patients by quantitative real-time polymerase chain reaction, and cytochrome b5–expression was detected by immunohistochemistry. Real-life androgen production after steroid conversion was measured using radiolabeled substrates.ResultsThe study identified the RA-associated intronic SNP rs1790834 in the CYB5A gene in one GWAS and confirmed the same SNP in our study. The minor allele reduced RA risk selectively in women (P = 4.1*10−3; OR = 0.63, 95% CI [0.46-0.86]). The protective effect was confined to rheumatoid factor-positive (OR = 0.53, [0.37-0.75]) and anti-cyclic citrullinated peptide-positive (OR = 0.58, [0.41-0.83]) cases, respectively. The protective allele doubles CYB5A mRNA-expression resulting in 2-3fold activation of steroid 17,20-lyase activity, and protective allele was accompanied by a higher density of cytochrome b5-positive cells in synovial tissue.ConclusionsCYB5A is the first RA susceptibility gene involved in androgen synthesis. Our functional analysis of SNP rs1790834 indicates that it contributes to the sex bias observed in RA.

Genetic Mechanisms Leading to Sex Differences Across Common Diseases and Anthropometric Traits

“…We found a strong contribution of hormone-responsive genes to several diseases and anthropometric traits, with examples of sex-interaction in this contribution (hypothesis 4). Recently, a gene involved in androgen synthesis was associated with RA (Stark et al 2015), and we show that androgen-responsive genes across the genome are enriched for association signal and sex differences. Although estrogen biology has been associated with comorbidities of T1D (Ryba et al 2011;Ryba-Stanisławowska et al 2014;Słomiński et al 2015), our results are the first to suggest a global impact on risk.…”

Androgen-Induced Immunosuppression

“…Two notable exceptions to this include women who inherited particular polymorphisms resulting in higher or lower androgen levels correlating with protection from disease or exacerbation, respectively. First, women predisposed to produce androgens in greater concentrations due to inheritance of a polymorphism in the CYB5A gene are protected from developing RA characterized by RF and antibodies to citrullinated proteins ( 141 ); and, second, women with lower serum androgens are more likely to develop a type of RA that is not responsive to combination therapy consisting of nonsteroidal anti-inflammatory drugs, low-dose prednisolone, methotrexate, and more than one of several other disease modifying anti-rheumatic drugs ( 142 ).…”

High susceptibility to collagen-induced arthritis in mice with progesterone receptors selectively inhibited in osteoprogenitor cells

“…Several genes outside the HLA region, including Stat4, the TRAF1-C5 locus, and PTPN22, have been reported to be associated with activation and progression of inflammation in RA [58][59][60][61][62]. Sex disparities in genetic susceptibility to RA are understudied, and only a polymorphism in the Cyb5a gene, which is related to androgen synthesis, has been found to be associated with risk for RA in women but not in men [63]. Recent studies have also suggested a role for epigenetic modifications in the activation and aggressiveness of synovial fibroblasts [64][65][66][67] and the X-encoded genes, Timp1 and IL-9R in RA [68].…”