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.
Highlights
Rheumatoid arthritis (RA) is characterized by decreased androgen levels, which was the first hormonal abnormality described
Our functional analysis of single nucleotide polymorphisms (SNP) rs1790834 indicates that it contributes to the sex bias observed in RA
As androgen levels in women are generally lower than in men, any additional decrease will disproportionately reduce the anti-inflammatory impact of androgens
Summary
Rheumatoid arthritis (RA) is characterized by decreased androgen levels, which was the first hormonal abnormality described. The decisive step governing androgen synthesis is the 17,20-lyase activity of the CYP17A1 gene-encoded enzyme cytochrome P450 17A1. Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that affects about 0.5 to 1.0% of the population. In RA there is a clear preponderance of affected women over men (3:1) [5]. This suggests that high concentrations of estrogens, low concentrations of Several androgens have anti-inflammatory properties. There is evidence that some RA patients of both sexes have reduced amounts of serum androgens, even years before disease onset [15,16]. In male RA patients, levels of serum testosterone are negatively correlated with disease severity [15]. A preponderance of serum glucocorticoids over serum androgens is known in many chronic inflammatory
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