title: CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women.
abstract: BACKGROUND
  Rheumatoid 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.
  
  
  METHODS
  Data 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  CYB5A 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.
authors.affiliation: Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany. klaus.stark@ukr.de.|Department of Genetic Epidemiology, University Regensburg, Regensburg, Germany. klaus.stark@ukr.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Stark
authors.affiliation: Laboratory of Experimental Rheumatology & Neuroendocrine Immunology, Department of Internal Medicine I, University Hospital Regensburg, BIOPARK 1, Josef-Engert-Straße 9, 93053, Regensburg, Germany. rainer.straub@ukr.de.
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Straub
authors.affiliation: National Institute of Rheumatic Diseases, Piešt'any, Slovakia. rovensky.jozef@nurch.sk.
authors.forename: Jozef
authors.initials: J
authors.lastname: Rovenský
authors.affiliation: National Institute of Rheumatic Diseases, Piešt'any, Slovakia. blazickova@nurch.sk.|Department of Laboratory Medicine, Faculty of Social Work and Health, University of Trnava, Trnava, Slovakia. blazickova@nurch.sk.
authors.forename: Stanislava
authors.initials: S
authors.lastname: Blažičková
authors.affiliation: Institute of Biochemistry II, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany. gabriele.eiselt@med.uni-jena.de.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Eiselt
authors.affiliation: Institute of Biochemistry II, Jena University Hospital - Friedrich Schiller University Jena, Jena, Germany. martin.schmidt@med.uni-jena.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000728:Androgens / Q000097:blood*; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D015786:Cytochromes b5 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D060888:Real-Time Polymerase Chain Reaction; D013583:Synovial Membrane / Q000378:metabolism; D055815:Young Adult
chemical_list: D000728:Androgens; C000594834:CYB5A protein, human; D004247:DNA; D015786:Cytochromes b5