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

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• 作者：Klaus Stark ; Rainer H Straub ; Jozef Rovensky…
• 刊名：Arthritis Research & Therapy
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：17
• 期：1
• 全文大小：979 KB
• 参考文献：1. Scott, DL, Wolfe, F, Huizinga, TW (2010) Rheumatoid arthritis. Lancet. 376: pp. 1094-108 CrossRef
  2. Eyre, S, Bowes, J, Diogo, D, Lee, A, Barton, A, Martin, P (2012) High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 44: pp. 1336-40 CrossRef
  3. Stahl, EA, Raychaudhuri, S, Remmers, EF, Xie, G, Eyre, S, Thomson, BP (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 42: pp. 508-14 CrossRef
  4. Straub, RH, Bijlsma, JW, Masi, A, Cutolo, M (2013) Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases -the 10-year update. Semin Arthritis Rheum. 43: pp. 392-404 CrossRef
  5. Symmons, D, Turner, G, Webb, R, Asten, P, Barrett, E, Lunt, M (2002) The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology (Oxford). 41: pp. 793-800 CrossRef
  6. Schmidt, M, Naumann, H, Weidler, C, Schellenberg, M, Anders, S, Straub, RH (2006) Inflammation and sex hormone metabolism. Ann NY Acad Sci 1069: pp. 236-46 CrossRef
  7. Cutolo, M, Accardo, S, Villaggio, B, Barone, A, Sulli, A, Balleari, E (1995) Androgen metabolism and inhibition of interleukin-1 synthesis in primary cultured human synovial macrophages. Mediat Inflamm. 4: pp. 138-45 CrossRef
  8. Danenberg, HD, Alpert, G, Lustig, S, Ben-Nathan, D (1992) Dehydroepiandrosterone protects mice from endotoxin toxicity and reduces tumor necrosis factor production. Antimicrob Agents Chemother. 36: pp. 2275-9 CrossRef
  9. Daynes, RA, Araneo, BA, Ershler, WB, Maloney, C, Li, GZ, Ryu, SY (1993) Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J Immunol 150: pp. 5219-30
  10. Kanda, N, Tsuchida, T, Tamaki, K (1997) Testosterone suppresses anti-DNA antibody production in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Arthritis Rheum. 40: pp. 1703-11 CrossRef
  11. Li, ZG, Danis, VA, Brooks, PM (1993) Effect of gonadal steroids on the production of IL-1 and IL-6 by blood mononuclear cells in vitro. Clin Exp Rheumatol. 11: pp. 157-62
  12. Straub, RH, Konecna, L, Hrach, S, Rothe, G, Kreutz, M, Sch?lmerich, J (1998) Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab. 83: pp. 2012-7 CrossRef
  13. Keller, ET, Chang, C, Ershler, WB (1996) Inhibition of NFkappaB activity through maintenance of IkappaB alpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem. 271: pp. 26267-75 CrossRef
  14. Toyoda, H, Takei, S, Formby, B (1996) Effect of 5-alpha dihydrotestosterone on T-cell proliferation of the female nonobese diabetic mouse. Proc Soc Exp Biol Med. 213: pp. 287-93 CrossRef
  15. Masi, AT, Aldag, JC, Jacobs, JW (2005) Rheumatoid arthritis: neuroendocrine immune integrated physiopathogenetic perspectives and therapy. Rheum Dis Clin North Am. 31: pp. 131-60 CrossRef
  16. Pikwer, M, Giwercman, A, Bergstrom, U, Nilsson, JA, Jacobsson, LT, Turesson, C (2014) Association between testosterone level
• 刊物主题：Rheumatology; Orthopedics;
• 出版者：BioMed Central
• ISSN：1478-6354

文摘

Introduction 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--.1*10?; OR--.63, 95% CI [0.46-0.86]). The protective effect was confined to rheumatoid factor-positive (OR--.53, [0.37-0.75]) and anti-cyclic citrullinated peptide-positive (OR--.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.