Ukr.Biochem.J. 2015; Том 87, № 2, березень-квітень, c. 26-40

doi: http://dx.doi.org/10.15407/ubj87.02.026

Асоціація алельних варіантів гена рецептора андрогенів (за кількістю CAG-повторів) з андрогензалежними гормонально-метаболічними показниками організму людини

25.05.2015   Uncategorized   No comments

 В. В. Корпачев, С. В. Мельниченко, Р. Г. Лукашова

ДУ «Інститут ендокринології та обміну речовин
ім. В. П. Комісаренка НАМН України», Київ;
e-mail: vitascovna@gmail.com

В огляді наведено сучасні уявлення про асоціацію різних (за кількістю CAG-повторів – цитозин-аденін-гуанін-повторів) алельних варіантів гена рецептора андрогенів (AR) зі зміною активності цього рецептора в організмі людини. Проаналізовано результати низки досліджень, в яких містяться суперечливі висновки щодо залежності функції андрогенів від кількості CAG-повторів у гені AR. Звернуто увагу на зв’язок між кількістю CAG-повторів та показниками вуглеводного і ліпідного обмінів в осіб обох статей.

Ключові слова: , , , , , ,

Посилання:

  1. Zitzmann M. Testosterone deficiency, insulin resistance and the metabolic syndrome. Nat Rev Endocrinol. 2009 Dec;5(12):673-81. Epub 2009 Oct 27. Review. PubMed, CrossRef
  2. Diedov I. I., Kalinchenko S. Yu. Aged-dependent androgen deficiency in men. Moscow: Practicheskaya meditsina, 2006; 240 p. (In Russian).
  3. Jääskeläinen J. Molecular biology of androgen insensitivity. Mol Cell Endocrinol. 2012 Apr 16;352(1-2):4-12. Epub 2011 Aug 17. Review.
    PubMed, CrossRef
  4. Carruthers M. Testosterone deficiency syndrome: cellular and molecular mechanism of action. Curr Aging Sci. 2013 Feb;6(1):115-24. Review. PubMed, CrossRef
  5. Tronko MD, Korpachova-Zinych OV. Steroid hormones and diabetes. Kyiv: Knyga-plus, 2010; 198 p. (In Russian).
  6. San Millán J. L., Cordớn M., Villuendas G., Sancho J., Peral B., Escobar-Morreale H. F. Association of polycystic ovary syndrome with genomic variations related to insulin resistance, type 2 diabetes mellitus, and obesity. J Clin Endocrinol Metab. 2004;89(6):2640-2646. CrossRef
  7. Barber TM, Franks S. Genetics of polycystic ovary syndrome. Front Horm Res. 2013;40:28-39. Review. PubMed, CrossRef
  8. Nieschlag E, Nieschlag S. Andrology: Male reproductive health and dysfunction. Springer, London. 2010. CrossRef
  9. Shang Y, Myers M, Brown M. Formation of the androgen receptor transcription complex. Mol Cell. 2002 Mar;9(3):601-10. PubMed, CrossRef
  10. Skyarpe P. A. Androgen receptor CAG and GGN polymorphisms in vivo and in vitro (University of Tromso, A thesis submitted for the degree of philosophiae doctor). Tromso, Norway. 2012; 59 p.
  11. Gao W, Bohl CE, Dalton JT. Chemistry and structural biology of androgen receptor. Chem Rev. 2005 Sep;105(9):3352-70. Review. PubMed, PubMedCentral, CrossRef
  12. Mauvais-Jarvis F. Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol Metab. 2011 Jan;22(1):24-33. Review. PubMed, PubMedCentral, CrossRef
  13. Dati E, Baroncelli GI, Mora S, Russo G, Baldinotti F, Parrini D, Erba P, Simi P, Bertelloni S. Body composition and metabolic profile in women with complete androgen insensitivity syndrome. Sex Dev. 2009;3(4):188-93. PubMed, CrossRef
  14. Kalyani RR, Dobs AS. Androgen deficiency, diabetes, and the metabolic syndrome in men. Curr Opin Endocrinol Diabetes Obes. 2007 Jun;14(3):226-34. Review. PubMed, CrossRef
  15. Yong EL, Ghadessy F, Wang Q, Mifsud A, Ng SC. Androgen receptor transactivation domain and control of spermatogenesis. Rev Reprod. 1998 Sep;3(3):141-4. Review. PubMed, CrossRef
  16. Gobinet J., Pujol N., Sultan C. Molecular action of androgens. Mol Cell Endocrinol. 2002;198:15-24. CrossRef
  17. Gelmann EP. Molecular biology of the androgen receptor. J Clin Oncol. 2002 Jul 1;20(13):3001-15. Review. PubMed, CrossRef
  18. Lindzey Y, Kumar MV, Grossman M, Young C, Tindal DJ. Molecular mechanisms of androgen action. Vitam Horm. 1994;49:383-432. CrossRef
  19. Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev. 1995 Jun;16(3):271-321. Review. PubMed, CrossRef
  20. Kuiper GG, Faber PW, van Rooij HC, van der Korput JA, Ris-Stalpers C, Klaasen P, Trapman J, Brinkman AO. Structural organization of the human androgen receptor gene. J Mol Endocrinol. 1989;2:R1-R4. CrossRef
  21. Claessens F, Denayer S, Van Tilborgh N, Kerkhofs S, Helsen C, Haelens A. Diverse roles of androgen receptor (AR) domains in AR-mediated signaling. Nucl Recept Signal. 2008 Jun 27;6:e008. Review. PubMed, PubMedCentral, CrossRef
  22. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991 Jul 4;352(6330):77-9. PubMed, CrossRef
  23. Wisniewski A. B., Migeon C. J., Meyer-Bahlburg H. F., Gearhart G. P., Berkovitz G. D., Brown T. R., Money J. Complete androgen insensitivity syndrome: Long-tern medical, surgical, and psychosexual outcome. J. Clin. Endocrinol. Metab. 2000;85:2664-2669.
  24. Zitzmann M. The role of the CAG repeat androgen receptor polymorphism in andrology. Front Horm Res. 2009;37:52-61. Review. PubMed, CrossRef
  25. Crabbe P, Bogaert V, De Bacquer D, Goemaere S, Zmierczak H, Kaufman JM. Part of the interindividual variation in serum testosterone level in healthy man reflects differences in androgen sensitivity and feedback set point: contribution of the androgen receptor polyglutamine tract polymorphism. J. Clin. Endocrinol. Metab. 2007;92(9):3604-3610. CrossRef
  26. Schoenberg MP, Hakimi YM, Wang S, Bove GS, Epstein JI, Fischbeck KH, Isaaks WB, Walsh PC, Barrack EP. Microsatellite mutation (CAG24→18) in the androgen receptor gene in human prostate cancer. Biochem Biophys Res Commun. 1994;198(1):74-80. CrossRef
  27. Klocker H, Gromoll J, Cato ACB. The androgen receptor: molecular biology. In “Testosterone, Action, Deficiency, Substitution”, Ed. Behre H. M., Cambridge, UK, Cambridge University Press, 2004:39-92. CrossRef
  28. Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994 Aug 11;22(15):3181-6. PubMed, PubMedCentral, CrossRef
  29. Beilin J, Ball EM, Favaloro JM, Zajac JD. Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. J Mol Endocrinol. 2000 Aug;25(1):85-96. PubMed, CrossRef
  30. Zitzmann M, Brune M, Kornmann B, Gromoll J, Junker R, Nieschlag E. The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males. Clin Endocrinol (Oxf). 2001 Nov;55(5):649-57. PubMed, CrossRef
  31. Ding D, Xu L, Menon M, Reddy GP, Barrack ER. Effect of a short CAG (glutamine) repeat on human androgen receptor function. Prostate. 2004 Jan 1;58(1):23-32. PubMed, CrossRef
  32. Madjunkova S, Eftimov A, Georgiev V, Petrovski D, Dimovski A, Plaseska-Karanfilska D. CAG Repeat Number in the Androgen Receptor Gene and Prostate Cancer. Balkan J Med Genet. 2012 Jun;15(1):31-6. PubMed, PubMed, CrossRef
  33. Tosh D, Panda B, Rao TN, Babu A, Satti V, Raghnadharao D, Singh L, Rao L. CAG and GGN repeat length polymorphism of androgen receptor gene in women with breast cancer: a case-control study from South India. J. Cancer Therapy. 2012;3:741-748. CrossRef
  34. Baculescu N. The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS. J Med Life. 2013 Mar 15;6(1):18-25. PubMed, PubMed
  35. Lin LH, Baracat MC, Maciel GA, Soares JM Jr, Baracat EC. Androgen receptor gene polymorphism and polycystic ovary syndrome. Int J Gynaecol Obstet. 2013 Feb;120(2):115-8. Review. PubMed, CrossRef
  36. Fesaĭ OA, Kravchenko SA, Tyrkus MIa, Makukh GV, Zinchenko VM, Strelko GV, Livshits LA. Androgen receptor CAG gene polymorphism in men with azoospermia and oligozoospermia in Ukraine. Tsitol Genet. 2009 Nov-Dec;43(6):45-51. Russian.  PubMed
  37. Fujimoto Y., Hirose R., Sakaguchi H., Tamaya T. Expression of size- polymorphic androgen receptor (AR) gene in ovarian endometriosis according the number of cytosine, adenine and guanine (CAG) repeat in AR alleles. Steroids. 1999;64(8):526-529. CrossRef
  38. Möhlig M, Jürgens A, Spranger J, Hoffmann K, Weickert MO, Schlösser HW, Schill T, Brabant G, Schüring A, Pfeiffer AF, Gromoll J, Schöfl C. The androgen receptor CAG repeat modifies the impact of testosterone on insulin resistance in women with polycystic ovary syndrome. Eur J Endocrinol. 2006;Jul;155(1):127-30. CrossRef
  39. Tirabassi G, Muti N, Corona G, Maggi M, Balercia G. Androgen receptor gene CAG repeat polymorphism independently influences recovery of male sexual function after testosterone replacement therapy in postsurgical hypogonadotropic hypogonadism. J. Sex Med. 2014;11:1302-1308. CrossRef
  40. Canale D, Caglieresi C, Moschini C, Liberati CD, Macchia E, Pinchera A, Martino E. Androgen receptor polymorphism (CAG repeats) and androgenicity. Clin Endocrinol (Oxf). 2005 Sep;63(3):356-61. Erratum in: Clin Endocrinol (Oxf). 2005 Oct;63(4):482. PubMed, CrossRef
  41. Davis-Dao CA, Tuazon ED, Sokol RZ, Cortessis VK. Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis. J Clin Endocrinol Metab. 2007 Nov;92(11):4319-26. PubMed
  42. Huhtaniemi IT, Pye SR, Limer KL, Thomson W., O’Neill TW, Platt H, Payne D, John SL, Jiang M, Boonen S, Borghs H, Vanderschueren D, Adams JE, Ward KA., Bartfai G, Casanueva F, Finn JD, Forti G, Giwercman A, Han ThS, Kula K, Lean ME J, Pendleton N, Punab M, Silman AJ, Wu FCW, European Male Ageing Study Group. Increased estrogen rather that decreased action is associated with longer androgen receptor CAG repeats. J. Clin. Endocrinol. Metab. 2009;94(1):277-284.
  43. Sverdlov ED. Considerations on structural molecular genetics. Look at the life through the genomic window. М.: Nauka, 2009; 525 p. (In Russian).
  44. Thomas PS Jr, Fraley GS, Damian V, Woodke LB, Zapata F, Sopher BL, Plymate SR, La Spada AR. Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy. Hum Mol Genet. 2006 Jul 15;15(14):2225-38. Erratum in: Hum Mol Genet. 2006 Oct 1;15(19):2972. Damien, Vincent [corrected to Damian, Vincent]. PubMed
  45. Ilarioshkin S. N. DNA-diagnostics and medico-genetic consultations. Moscow: Meditsinskoye informatsionnoye agentstvo. 2004; 207 p. (In Russian).
  46. Esteban E, Rodon N, Via M, Gonzales-Perez E, Santamaria J., Dugoujon JM, Chennawi FE, Melhaoui M, Cherkaoui M, Vona G, Harich N, Maral P. Androgen receptor CAG and GGC polymorphism in Mediterranean: repeat dynamics and population relationships. J. Hum. Genet. 2006;51(2):129-136.
  47. Namiki M, Ueno S, Kitagawa Y, Fukagai T, Akaza H. Effectiveness and adverse effects of hormonal therapy for prostate cancer: Japanese experience and perspective. Asian J Androl. 2012 May;14(3):451-7. Epub 2012 Mar 26. Review. PubMed, PubMedCentral, CrossRef
  48. Sasaki M, Kaneuchi M, Sakuragi N, Fujimoto S, Carroll PR, Dahiya R. The polyglycine and polyglutamine repeats in the androgen receptor gene in Japanese and Caucasian populations. Biochem Biophys Res Commun. 2003 Dec 26;312(4):1244-7. PubMed
  49. Colangelo LA, Sharp L, Kopp P, Scholtens D, Chiu BC, Liu K, Gapstur SM. Total testosterone, androgen receptor polymorphism, and depressive symptoms in young black and white men: the CARDIA Male Hormone Study. Psychoneuroendocrinology. 2007 Sep-Nov;32(8-10):951-8. PubMed, PubMedCentral
  50. Schneider G, Zitzmann M, Gromoll J, Ladwig KH, Berger K. The relation between sex hormone levels, the androgen receptor CAGn-polymorphism and depression and mortality in older men in a community study. Psychoneuroendocrinology. 2013;38(10):2083-2090.
  51. T’Sjoen GG, De Vos S, Goemaere S, Van Pottelbergh I, Dierick M, Van Heeringen C, Kaufman JM. Sex steroid level, androgen receptor polymorphism, and depressive symptoms in healthy elderly men. J Am Geriatr Soc. 2005 Apr;53(4):636-42. PubMed
  52. Seidman SN, Araujo AB, Roose SP, McKinlay JB. Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biol Psychiatry. 2001 Sep 1;50(5):371-6. PubMed
  53. Geng YG, Su QR, Su LY, Chen Q, Ren GY, Shen SQ, Yu AY, Xia GY. Comparison of the polymorphisms of androgen receptor gene and estrogen alpha and beta gene between adolescent females with first-onset major depressive disorder and controls. Int J Neurosci. 2007 Apr;117(4):539-47. PubMed
  54. Lind JM, Chiu C, Ingles J, Yeates L, Humphries SE, Heather AK, Semsarian C. Sex hormone receptor gene variation associated with phenotype in male hypertrophic cardiomyopathy patients. J Mol Cell Cardiol. 2008 Aug;45(2):217-22. PubMed, CrossRef
  55. Alevizaki M, Cimponeriu AT, Garofallaki M, Sarika HL, Alevizaki CC, Papamichael C, Philippou G, Anastasiou EA, Lekakis JP, Mavrikakis M. The androgen receptor gene CAG polymorphism is associated with the severity of coronary artery disease in men. Clin Endocrinol (Oxf). 2003 Dec;59(6):749-55. PubMed
  56. Zitzmann M, Nieschlag E. Androgens and vascular function. J Endocrinol Invest. 2003 Aug;26(8):767-9. PubMed
  57. MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk. Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy. Int J Cancer. 2010 Jun 15;126(12):2935-46. PubMed, CrossRef
  58. Kalyani RR, Franco M, Dobs AS, Ouyang P, Vaidya D, Bertoni A, Gapstur SM, Golden SH. The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. J Clin Endocrinol Metab. 2009 Nov;94(11):4127-35. PubMed, PubMedCentral, CrossRef
  59. Brum IS, Spritzer PM, Paris F, Maturana MA, Audran F, Sultan C. Association between androgen receptor gene CAG repeat polymorphism and plasma testosterone levels in postmenopausal women. J Soc Gynecol Investig. 2005 Feb;12(2):135-41. PubMed
  60. Rexrode KM, Ridker PM, Hegener HH, Buring JE, Manson JE, Zee RY. Genetic variation of the androgen receptor and risk of myocardial infarction and ischemic stroke in women. Stroke. 2008 May;39(5):1590-2. PubMed, CrossRef
  61. Trevison TG, Shackelton R, Araujo AB, Morley JE, Williams RE, Clark RV, McKinlay JB. Frailty, serum androgens, and the CAG repeat polymorphism: results from the Massachusetts male aging study. J. Clin. Endocrinol. Metab. 2010;95(6):2746-2754.
  62.  Voorhoeve PG, Mechelen W, Uitterlinden AG, Delemarre-van de Waal HA, Lamberts SW. Androgen receptor gene CAG repeat polymorphism in longitudinal height and body composition in children and adolеscents. Clin. Endocrinol. (Oxf). 2011;74(6):732-735.
  63. Yeap BB, Chubb SA, Hyde Z, Jamrozik K, Hankey GJ, Flicker L, Norman PE. Lower serum testosterone is independently associated with insulin resistance in non-diabetic older men: the Health In Men Study. Eur J Endocrinol. 2009 Oct;161(4):591-8. PubMed, CrossRef
  64. Ponce-González JG, Guadalupe-Grau A, Rodríguez-González FG, Dorado C, Olmedillas H, Fuentes T, Rodríguez-García L, Díaz-Chico BN, Calbet JA. Androgen receptor gene polymorphisms and the fat-bone axis in young men and women. J Androl. 2012 Jul-Aug;33(4):644-50. PubMed, CrossRef
  65. Rodrígez-González G., Ramírez-Moreno R., Pérez P., Bilbao P., López-Ríos L., Díaz-Chico J. C., Lara P. C., Serra-Majem L., Chirino R., Díaz-Chico B. N. The GGN and CAG repeat polymorphisms in the exon-1 of the androgen receptor gene are, respectively, associated with insulin resistance in men and with dyslipidemia in women. J Steroid Biochem. Mol. Biol. 2009;113:202-208.
  66. Saad F. The role of testosterone in type 2 diabetes and metabolic syndrome in men. Arq Bras Endocrinol Metabol. 2009 Nov;53(8):901-7. Review. PubMed
  67. Li C, Ford ES, Li B, Giles WH, Liu S. Association of testosterone and sex hormone-binding globulin with metabolic syndrome and insulin resistance in men. Diabetes Care. 2010 Jul;33(7):1618-24. PubMed, PubMedCentral, CrossRef
  68. Zitzmann M, Mattern A, Hanison J, Gooren L, Jines H, Maggi M. IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1438. J. Sex. Med. 2013;10(2):579-588.
  69. Stanworth RD, Kapoor D, Channer KS, Jones TH. Dyslipidaemia is associated with testosterone, oestradiol and androgen receptor CAG repeat polymorphism in men with type 2 diabetes. Clin Endocrinol (Oxf). 2011 May;74(5):624-30. PubMed, CrossRef
  70. Möhlig M., Arafat A. M., Osterhoff M. A., Isken F., Weickert M. O., Spranger J., Pfeiffers A. F. H., Schöfl Ch. Androgen receptor CAG repeat length polymorphism modifies the impact of testosterone on insulin sensitivity in men. Eur. J. Endocrinol. 2011;164(6):1013-1018.
  71. Kapoor D, Clarke S, Stanworth R, Channer KS, Jones TH. The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2007 May;156(5):595-602. PubMed
  72. Zitzmann M, Gromoll J, von Eckardstein A, Nieschlag E. The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men. Diabetologia. 2003 Jan;46(1):31-9. PubMed
  73. Zitzmann M. Effects of testosterone replacement and its pharmacogenetics on physical performance and metabolism. Asian J Androl. 2008 May;10(3):364-72. Review. PubMed, CrossRef
  74. Wiwanitkit V. CAG repeat polymorphism in the androgen receptor: a study on the effect of different numbers of repeats using Gene Ontology technique. Fertil Steril. 2009 Jan;91(1):e5-6. PubMed, CrossRef
  75. Nielsen TL, Hagen C, Wraae K, Bathum L, Larsen R, Brixen K, Andersen M. The impact of the CAG repeat polymorphism of the androgen receptor gene on muscle and adipose tissues in 20-29-year-old Danish men: Odense Androgen Study. Eur J Endocrinol. 2010 Apr;162(4):795-804. PubMed, CrossRef
  76. Walsh S, Zmuda JM, Cauley JA, Shea PR, Metter EJ, Hurley BF, Ferrell RE, Roth SM. Androgen receptor CAG repeat polymorphism is associated with fat-free mass in men. J Appl Physiol (1985). 2005 Jan;98(1):132-7. PubMed
  77. Van Pottelbergh I, Lumbroso S, Goemaere S, Sultan C, Kaufman JM. Lack of influence of the androgen receptor gene CAG-repeat polymorphism on sex steroid status and bone metabolism in elderly men. Clin Endocrinol (Oxf). 2001 Nov;55(5):659-66. PubMed
  78. Krithivas K, Yurgalevitch SM, Mohr BA, Wilcox CJ, Batter SJ, Brown M, Longcope C, McKinlay JB, Kantoff PW. 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. 1999 Jul;162(1):137-42. PubMed
  79. Stanworth RD, Akhtar S, Channer KS, Jones TH. The role of androgen receptor CAG repeat polymorphism and other factors which affect the clinical response to testosterone replacement in metabolic syndrome and type 2 diabetes: TIMES2 sub-study. Eur J Endocrinol. 2013 Dec 21;170(2):193-200. Print 2014 Feb. PubMed, CrossRef
  80. Skjaerpe PA, Giwercman YL, Giwercman A, Svartberg J. Androgen receptor gene polymorphism and sex hormones in elderly men: the Tromsø study. Asian J Androl. 2009 Mar;11(2):222-8. Epub 2009 Jan 12. PubMed, PubMedCentral, CrossRef
Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.