Skip to main content

Advertisement

SpringerLink
Log in

Association of tri-nucleotide (CAG and GGC) repeat polymorphism of androgen receptor gene in Taiwanese women with refractory or remission rheumatoid arthritis

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

We investigated the relationship between CAG and GGC repeat polymorphism of the androgen receptor (AR) gene and rheumatoid arthritis (RA) in female patients with different disease subtypes. This case-control study enrolled 215 women in three groups: RA patients refractory to standardized therapy (n = 51); RA patients at complete remission phase (n = 60); and healthy controls (n = 104). CAG and GGC repeat lengths were determined by automated fluorescence-based DNA fragment-sizing method. Demographic data, allele lengths, allele distribution, and zygosity status of CAG/GGC repeats were assessed for the three groups. Refractory RA patients tend to have a significantly younger onset age of RA and more elevated erythrocyte sedimentation rates than do remission RA patients. Mean and median values of CAG and GGC repeat lengths are similar in both RA and control patients. However, RA patients harboring any long CAG alleles with more than 23 repeats had an increased risk of a refractory course, whereas differences in risk were not observed between these patients and RA subtypes harboring any long GGC alleles with more than 16 repeats. In addition, the homozygous frequency of CAG but not GGC alleles was lower in refractory RA than in remission RA patients or in controls (p = 0.042). Neither CAG nor GGC repeat lengths had a significant relationship with rheumatoid factor reactivity. Our observations indicate that short CAG repeats of the AR gene with higher transactivation activity may have protective effects against refractory course of RA development and that homozygous frequency of CAG alleles may be involved in the disease remission subtype. In contrast, lack of association of GGC polymorphism and RA was also observed. Together, these data imply that CAG but not GGC alleles in the AR polymorphism may play an important role in modulating the disease pattern of RA among Taiwanese women.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Oliver JE, Worthington J, Silman AJ (2006) Genetic epidemiology of rheumatoid arthritis. Curr Opin Rheumatol 18:141–146

    Article  PubMed  Google Scholar 

  2. Turesson C, Matteson EL (2006) Genetics of rheumatoid arthritis. Mayo Clin Proc 81:94–101

    Article  CAS  PubMed  Google Scholar 

  3. Ansar Ahmed S, Penhale WJ, Talal N (1985) Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action. Am J Pathol 121:531–551

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Tanriverdi F, Silveira LF, MacColl GS, Bouloux PM (2003) The hypothalamic-pituitary-gonadal axis: immune function and autoimmunity. J Endocrinol 176:293–304

    Article  CAS  PubMed  Google Scholar 

  5. Cutolo M, Castagnetta L (1996) Immunomodulatory mechanisms mediated by sex hormones in rheumatoid arthritis. Ann N Y Acad Sci 784:237–251

    Article  CAS  PubMed  Google Scholar 

  6. Masi AT, Chatterton RT, Aldag JC (1999) Perturbations of hypothalamic-pituitary-gonadal axis and adrenal androgen functions in rheumatoid arthritis: an odyssey of hormonal relationships to the disease. Ann N Y Acad Sci 876:53–63

    Article  CAS  PubMed  Google Scholar 

  7. Masi AT, Feigenbaum SL, Chatterton RT (1995) Hormonal and pregnancy relationships to rheumatoid arthritis: convergent effects with immunological and microvascular systems. Semin Arthritis Rheum 25:1–27

    Article  CAS  PubMed  Google Scholar 

  8. Cutolo M (2002) Sex hormone adjuvanting therapy in rheumatoid arthritis. Lupus 11:670–674

    Article  CAS  PubMed  Google Scholar 

  9. Pope JE, Joneja M, Hong P (2002) Anti-androgen treatment of prostatic carcinoma may be a risk factor for development of rheumatoid arthritis. J Rheumatol 29:2459–2462

    PubMed  Google Scholar 

  10. Booji A, Biewenga-Booji CM, Huber-Bruning O, Cornelis C, Jacobs JW, Bijlsma JW (1996) Androgens as adjuvant treatment in postmenopausal female patients with rheumatoid arthritis. Ann Rheum Dis 55:811–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Khalkhali EZ, Moore TL, Hendrix MJ (1998) Reduced levels of testosterone and dehydroepiandrosterone sulphate in the serum and synovial fluid of juvenile rheumatoid arthritis patients correlates with disease severity. Clin Exp Rheumatol 16:753–756

    Google Scholar 

  12. Hedman M, Nilsson E, de la Torre B (1992) Low blood and synovial fluid levels of sulpho-conjugated steroids in rheumatoid arthritis. Clin Exp Rheumatol 10:25–30

    CAS  PubMed  Google Scholar 

  13. Tengstrand B, Carlstrom K, Fellander TL, Hafstrom I (2003) Abnormal levels of serum dehydroepiandrosterone, estrone, and estradiol in men with rheumatoid arthritis: high correlation between serum estradiol and current degree of inflammation. J Rheumatol 30:2338–2343

    CAS  PubMed  Google Scholar 

  14. Chang CS, Kokontis J, Liao ST (1988) Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 240:324–326

    Article  CAS  PubMed  Google Scholar 

  15. Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM (1988) Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 240:327–330

    Article  CAS  PubMed  Google Scholar 

  16. Chamberlain NL, Driver ED, Miesfeld RL (1994) The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22:3181–3186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Choong CS, Kemppainen JA, Zhou ZX, Wilson EM (1996) Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol Endocrinol 10:1527–1535

    CAS  PubMed  Google Scholar 

  18. Ding D, Xu L, Menon M, Reddy GPV, Barrack ER (2005) Effect of GGC (glycine) repeat length polymorphism in the human androgen receptor on androgen action. Prostate 62:133–139

    Article  CAS  PubMed  Google Scholar 

  19. Doyu M, Sobue G, Mukai E, Kachi T, Yasuda T, Mitsuma T, Takahashi A (1992) Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene. Ann Neurol 32:707–710

    Article  CAS  PubMed  Google Scholar 

  20. Alevizaki M, Cimponeriu AT, Garofallaki M, Sarika HL, Alevizaki CC, Papamichael C, Philippou G, Anastasiou EA, Lekakis JP, Mavrikakis M (2003) The androgen receptor gene CAG polymorphism is associated with the severity of coronary artery disease in men. Clin Endocrinol 59:749–755

    Article  CAS  Google Scholar 

  21. Westberg L, Baghaei F, Rosmond R, Hellstrand M, Landen M, Jansson M, Holm G, Bjorntorp P, Eriksson E (2001) Polymorphisms of the androgen receptor gene and the estrogen receptor beta gene are associated with androgen levels in women. J Clin Endocrinol Metab 86:2562–2568

    CAS  PubMed  Google Scholar 

  22. Kawasaki T, Ushiyama T, Ueyama H, Inoue K, Mori K, Ohkubo I, Hukuda S (1999) Polymorphic CAG repeats of the androgen receptor gene and rheumatoid arthritis. Ann Rheum Dis 58:500–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lo SF, Huang CM, Tsai CH, Chen WC, Lai CC, Tsai Y, Tsai FJ (2006) Androgen receptor gene polymorphism and rheumatoid arthritis in Taiwan. Clin Exp Rheumatol 24:209–210

    PubMed  Google Scholar 

  24. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    Article  CAS  PubMed  Google Scholar 

  25. National Institute for Clinical Excellence. Guidance on the use of etanercept and infliximab for rheumatoid arthritis. NICE Technology Appraisal Guidance No. 36. London: National Institute for Clinical Excellence. [Internet. Accessed 2002 March]. Available from http://www.nice.org.uk/pdf/RA-PDF.pdf

  26. Ledingham J., Deighton C. on behalf of the British Society for Rheumatology Standards, Guidelines and Audit Working Group (2005) Update on the British Society for Rheumatology guidelines for prescribing TNF-α blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 44:157–163

    Article  CAS  PubMed  Google Scholar 

  27. Prevoo MLL, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LBA, van Riel PLCM (1995) Modified disease activity scores that include twenty-eight-joint counts. Arthritis Rheum 38:44–48

    Article  CAS  PubMed  Google Scholar 

  28. Pinals RS, Masi AT, Larsen RA (1981) Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 24:1308–1315

    Article  CAS  PubMed  Google Scholar 

  29. Irvine RA, Yu MC, Ross RK, Coetzee GA (1995) The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res 55:1937–1940

    CAS  PubMed  Google Scholar 

  30. Spurdle AB, Dite GS, Chen X, Mayne CJ, Southey MC, Batten LE, Chy H, Trute L, McCredie MR, Giles GG, Armes J, Venter DJ, Hopper JL, Chenevix-Trench G (1999) Androgen receptor exon 1 CAG repeat length and breast cancer in women before age forty years. J Natl Cancer Inst (Bethesda) 91:961–966

    Article  CAS  Google Scholar 

  31. Rebbeck TR, Kantoff PW, Krithivas K, Neuhausen S, Blackwood MA, Godwin AK, Daly MB, Narod SA, Garber JE, Lynch HT, Weber BL, Brown M (1999) Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet 64:1371–1377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yeh SH, Chang CF, Shau WY, Chen YW, Hsu HC, Lee PH, Chen DS, Chen PJ (2002) Dominance of functional androgen receptor allele with longer CAG repeat in hepatitis B virus-related female hepatocarcinogenesis. Cancer Res 62:4346–4351

    CAS  PubMed  Google Scholar 

  33. Sasaki M, Kaneuchi M, Sakuragi N, Fujimoto S, Carroll PR, Dahiya R (2003) The polyglycine and polyglutamine repeats in the androgen receptor gene in Japanese and Caucasian populations. Biochem Biophys Res Commun 312:1244–1247

    Article  CAS  PubMed  Google Scholar 

  34. Fujii K, Okiura T, Nishimura K, Orimoto C, Nishimukai H (2003) Short tandem repeat typing in exon 1 of the androgen receptor gene. Leg Med (Tokyo) 5(Suppl 1):201–203

    Article  Google Scholar 

  35. Kang HY, Tsai MY, Chang C, Huang KE (2003) Mechanisms and clinical relevance of androgens and androgen receptor actions. Chang Gung Med J 26:388–402

    PubMed  Google Scholar 

  36. Janne OA, Palvimo JJ, Kallio P, Mehto M (1993) Androgen receptor and mechanism of androgen action. Ann Med 25:83–89

    Article  CAS  PubMed  Google Scholar 

  37. Cutolo M, Accardo S, Villaggio B, Clerico P, Indiveri F, Carruba G, Fecarotta E, Castagnetta L (1992) Evidence for the presence of androgen receptors in the synovial tissue of rheumatoid arthritis patients and healthy controls. Arthritis Rheum 35:1007–1015

    Article  CAS  PubMed  Google Scholar 

  38. Ishizuka M, Hatori M, Suzuki T, Miki Y, Darnel AD, Tazawa C, Sawai T, Uzuki M, Tanaka Y, Kokubun S, Sasano H (2004) Sex steroid receptors in rheumatoid arthritis. Clin Sci (Lond) 106:293–300

    Article  CAS  Google Scholar 

  39. Krithivas K, Yurgalevitch SM, Mohr BA, Wilcox CJ, Batter SJ, Brown M, Longcope C, McKinlay JB, Kantoff PW (1999) Evidence that the CAG repeat in the androgen receptor gene is associated with the age-related decline in serum androgen levels in men. J Endocrinol 162:137–142

    Article  CAS  PubMed  Google Scholar 

  40. Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, Brufsky A, Talcott J, Hennekens CH, Kantoff PW (1997) The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A 94:3320–3323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sasaki M, Dahiya R, Fujimoto S, Ishikawa M, Oshimura M (2000) The expansion of the CAG repeat in exon 1 of the human androgen receptor gene is associated with uterine endometrial carcinoma. Mol Carcinog 27:237–244

    Article  CAS  PubMed  Google Scholar 

  42. Sasaki M, Karube A, Karube Y, Watari M, Sakuragi N, Fujimoto S, Dahiya R (2005) GGC and StuI polymorphism on the androgen receptor gene in endometrial cancer patients. Biochem Biophys Res Commun 329:100–104

    Article  CAS  PubMed  Google Scholar 

  43. Dietzsch E, Laubscher R, Parker MI (2003) Esophageal cancer risk in relation to GGC and CAG trinucleotide repeat lengths in the androgen receptor gene. Int J Cancer 107:38–45

    Article  CAS  PubMed  Google Scholar 

  44. Suter NM, Malone KE, Daling JR, Doody DR, Ostrander EA (2003) Androgen receptor (CAG)n and (GGC)n polymorphisms and breast cancer risk in a population-based case-control study of young women. Cancer Epidemiol Biomark Prev 12:127–135

    CAS  Google Scholar 

  45. Schmidt BJ, Greenberg CR, Allingham-Hawkins DJ, Spriggs EL (2002) Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women. Neurology 59:770–772

    Article  PubMed  Google Scholar 

  46. Racchi O, Mangerini R, Rapezzi D, Rolfo M, Gaetani GF, Ferraris AM (1998) X chromosome inactivation patterns in normal females. Blood Cells Mol Diseases 24:439–447

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Sheng-Nan Lu and Dr. Suh-Hang Hank Juo for their helpful comments on the manuscript and Miss Ming-Chi Yang for technical assistance. This study was supported by Chang Gung Memorial Hospital (grant no. CMRP83050 and CMRPG850111). The authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. Graduate Institute of Clinical Medical Sciences, Chang Gung University, 16F-4, No. 123-9, Ta-Pei Road, Niao-Sung Hsiang, 833, Kaohsiung Hsein, Taiwan

    S. F. Yu & H. Y. Kang

  2. Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, 123, Ta-Pei Road, Niao-Sung Hsiang, 833, Kaohsiung Hsein, Taiwan

    S. F. Yu, T. T. Cheng, H. M. Lai, Y. C. Chen, C. K. Chiu, K. M. Lin & C. J. Chen

  3. Program for Population Genetics, Harvard School of Public Health, Boston, MA, USA

    Y. H. Hsu

  4. Departments of Pathology, Urology, Radiation Oncology, University of Rochester, Rochester, NY, USA

    C. Chang

  5. Center for Menopause and Reproductive Medicine Research, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan

    H. Y. Kang

Authors
  1. S. F. Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. T. Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. H. Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. M. Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y. C. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. K. Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K. M. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C. J. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H. Y. Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to C. J. Chen or H. Y. Kang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yu, S.F., Cheng, T.T., Hsu, Y.H. et al. Association of tri-nucleotide (CAG and GGC) repeat polymorphism of androgen receptor gene in Taiwanese women with refractory or remission rheumatoid arthritis. Clin Rheumatol 26, 2051–2058 (2007). https://doi.org/10.1007/s10067-007-0616-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-007-0616-z

Keywords

Search

Navigation