DEVELOPMENT OF POLYCYSTIC OVARY SYNDROME: GENETIC ASPECTS


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Abstract

Objective. To study the data available in the modem literature on the genetic markers for the development of polycystic ovary syndrome (POS). Materials and methods. Publications on the candidate genes of POS development, which were associated with impaired androgen biosynthesis, ovulatory dysfunction, and metabolic disturbances, were reviewed. Results. More than 100 candidate genes are known to be involved in the development of POS. Full-genomic studies in a Chinese female population revealed 11 new genetic markers for POS, which corresponded to the THADA, DENND1A, INSR, C9orf3, YAP1, LHCGR, FSHR, HMG2, T0X3, SUOX, and RAB5B genes, Genetic studies conducted in the USA and Western Europe confirmed an interethnic similarity by 8 genes. Conclusion. Identification of new polymorphic loci associated with POS in women of different populations substantiates that it is expedient to conduct further genetic clinical, associative, and functional investigations to study the contribution of these genes to the development of a spectrum of reproductive and metabolic disorders.

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About the authors

A. A Naidukova

Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia

post-graduate, department of gynecological endocrinology Moscow 117997, Ac. Oparina str. 4, Russia

E. K Kaprina

Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia

post-graduate, department of gynecological endocrinology Moscow 117997, Ac. Oparina str. 4, Russia

A. E Donnikov

Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia

Email: a_donnikov@oparina4.ru
Candidate of Medical Sciences, Senior Researcher, Laboratory of molecular genetic research methods Moscow 117997, Ac. Oparina str. 4, Russia

G. E Chernukha

Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia

Email: g_chemukha@oparina4.ru
a doctor of medical sciences, professor, head of department of Gynecological Endocrinology Moscow 117997, Ac. Oparina str. 4, Russia

References

  1. National Institutes of Health. Evidence-based Methodology Workshop on Polycystic Ovary Syndrome. December 3-5, 2012. Final report. Executive summery.
  2. Diamanti-Kandarakis E., Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr. Rev. 2012; 33(6): 981-1030.
  3. Legro R.S., Kunselman A.R., Dodson W.C., Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J. Clin. Endocrinol. Metab. 1999; 84(1): 165-9.
  4. Apridonidze I, Essah P.A., Luorno M.J., Nestler J.E. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2005; 90(4): 1929-35.
  5. Vink J.M., Sadrzadeh S., Lambalk C.B., Boomsma D.I. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J. Clin. Endocrinol. Metab. 2006; 91(6): 2100^.
  6. YildizB.O., YaraliH., OguzH., BayraktarM. Glucose intolerance, insulin resistance, and hyperandrogenemia in first degree relatives of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2003; 88(5): 2031-6.
  7. Kenyon C. A pathway that links reproductive status to lifespan in Caenorhabditis elegans. Ann. N. Y. Acad. Sci. 2010; 1204: 156-62.
  8. Holte JBergh T, Beme C., Berglund L., Lithell H. Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance. J. Clin. Endocrinol. Metab. 1994; 79(5): 1052-8.
  9. Simoni M., Tempfer C.B., Destenaves B., Fauser B.C. Functional genetic polymorphisms and female reproductive disorders: Part I: Polycystic ovary syndrome and ovarian response. Hum. Reprod. Update. 2008; 14(5): 459-84.
  10. Ruan Y, Ma J., Xie X. Association of IRS-1 and IRS-2 genes polymorphisms with polycystic ovary syndrome: a meta-analysis. Endocr. J. 2012; 59(7): 601-9.
  11. Сухих FT, Бирюкова A.M., Назаренко T.A., ЗахаржевскаяН.Б.,Дуринян Э.Р., Генерозов Э.В., Говорун В.М. Анализ ассоциативных связей полиморфизмов генов с синдромом поликистозных яичников и эндокринно-метаболическими нарушениями. Акушерство и гинекология. 2011; 5: 49-53.
  12. Shao W., Wang D. , Chiang Y. T., Ip W., Zhu L., Xu F. et al. The Wnt signaling pathway effector TCF7L2 controls gut and brain proglucagon gene expression and glucose homeostasis. Diabetes. 2013; 62(3): 789-800.
  13. Biyasheva A., Legro P.S., Dunaif A., Urbanek M. Evidence for association between polycystic ovary syndrome (PCOS) and TCF7L2 and glucose intolerance in women with PCOS and TCF7L2. J. Clin. Endocrinol. Metab. 2009; 94(7): 2617-25.
  14. Shen W.J., Li T.R., Hu Y.J., Liu H.B., Song M. Relationships betweenTCF7L2 genetic polymorphisms and polycystic ovary syndrome risk: a meta-analysis. Metab. Syndr. Relat. Disord. 2014; 12(4): 210-9.
  15. Song do K., Lee H., Oh J.Y., Hong Y.S., Sung Y.A. FTO gene variants are associated with PCOS susceptibility and hyperandrogenemia in young Korean women. Diabetes Metab. J. 2014; 38(4): 302-10.
  16. LiT., WuK., You L., Xing X, WangP., CuiL. etal. Common variant rs9939609 in gene FTO confers risk to polycystic ovary syndrome. PLoS One. 2013; 8(7): e66250.
  17. Petry C.J., Ong K.K., Michelmore K.F., Artigas S., Wingate D.L., Balen AH. et al. Association of aromatase (CYP19) gene variation with features of hyperan- drogenism in two populations of young women. Hum. Reprod. 2005; 20(7): 1837-43.
  18. Baghaei F, Rosmond R., Westberg L., Hellstrand M., Eriksson E., Holm G., Bjorntorp P. The CYP19 gene and associations with androgens and abdominal obesity in premenopausal women. Obes. Res. 2003; 11(4): 578-85.
  19. Xita N., Lazaros L., Georgiou I., Tsatsoulis A. CYP19 gene: a genetic modifier of polycystic ovary syndrome phenotype. Fertil. Steril. 2010; 94(1): 250-4.
  20. Pirez M.S., Cerrone G.E., Benencia H., Mdrquez N., De Piano E., Frechtel G.D. Polymorphism in CYPllalpha and CYP17 genes and the etiology of hyperan- drogenism in patients with polycystic ovary syndrome. Medicina (B Aires). 2008; 68(2): 129-34.
  21. Ding D., Xu L., Menon M., Reddy G.P., Barrack E.R. Effect of a short CAG (glutamine) repeat on human androgen receptor function. Prostate. 2004; 58( 1): 23-32.
  22. Schilling A.N., WelpA., GromollJ., Zitzjnann M., SonntagB., NieschlagE. et al. Role of the CAG repeat polymorphism of the androgen receptor gene in polycystic ovary syndrome (PCOS). Exp. Clin. Endocrinol. Diabetes. 2012; 120(2): 73-9. doi: 10.1055/s-0031-1291343.
  23. Dasgupta S., Sirisha P.V., NeelaveniK., Anuradha K., Reddy A.G., ThangarajK., Reddy B.M. Androgen receptor CAG repeat polymorphism and epigenetic influence among the south Indian women with Polycystic Ovary Syndrome. PLoS One. 2010; 5(8): ЄІ2401. doi: 10.1371/journal.pone.0012401.
  24. Андреева E.H., Сешчева T.B., Веснина А.Ф., Прокофьев С.А., Иванова О.Н., Карпова Е.А., Кириллов М.Ю., Ледов И.И. Молекулярно-генетические аспекты патогенеза СПКЯ. Проблемы репродукции. 2007; 13(6): 29-35.
  25. Skrgatic L., Baldani D.P., Сете J.Z., Ferk P, Gersak K. CAG repeat polymorphism in androgen receptor gene is not directly associated with polycystic ovary syndrome but influences serum testosterone levels. J. Steroid Biochem. Mol. Biol. 2012; 128(3-5): 107-12. doi: 10.1016/j.jsbmb.2011.11.006.
  26. Shah N.A., Antoine H.J., Pall M., Taylor K.D., Azziz R.r Goodarzi M.O. Association of androgen receptor CAG repeat polymorphism and polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2008; 93(5): 1939-45. doi: 10.1210/ jc.2008-0038.
  27. Hickey T, Chandy A., Norman R.J. The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2002; 87(1): 161-5.
  28. Чернуха Г.Е., Немова Ю.И., Блинова И.В., Руденко В.В. Представленность неслучайной инактивации хромосомы X и полиморфизма гена андрогенного рецептора при различных фенотипах синдрома поликистозных яичников. Акушерство и гинекология. 2013; 4: 38-43.
  29. HeardE., Clerc P., AvnerP. X-chromosome inactivation in mammals. Annu. Rev. Genet. 1997; 31:571-610.
  30. Calvo R.M., Asuncion M., Sancho J., San Millan J.L., Escobar-MorrealeH.F. The role of the CAG repeat polymorphism in the androgen receptor gene and of skewed X-chromosome inactivation, in the pathogenesis of hirsutism. J. Clin. Endocrinol. Metab. 2000; 85(4): 1735-40.
  31. Xita N., Tsatsoulis A., Chatzikyriakidou A., Georgiou I. Association of the (TAAAA)n repeat polymorphism in the sex hormone-binding globulin (SHBG) gene with polycystic ovary syndrome and relation to SHBG serum levels. J. Clin. Endocrinol. Metab. 2003; 88(12): 5976-80.
  32. Lindstedt G., Lundberg PA., Lapidus L., Lundgren H., Bengtsson C., Bjorntorp P. Low sex-hormone-binding globulin concentration as independent risk factor for development of NIDDM: 12-year follow-up of population study of women in Gothenborg, Sweden. Diabetes. 1991; 40(1): 123-8.
  33. Lapidus L., Lindstedt G., Lundberg PA., Bengtsson C., Gredmark T. Concentrations of sex-hormone-binding-globulin and corticosteroid binding globulin in serum in relation to cardiovascular risk factors and to 12-year incidence of cardiovascular disease and overall mortality in postmenopausal women. Clin. Chem. 1986; 32(1, Ptl): 146-52.
  34. Chen Z.J., Zhao H., He L., Shi Y, Qin Y., Shi Y. et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2pl6.3, 2p21 and 9q33.3. Nat. Genet. 2011; 43(1): 55-9.
  35. Shi Y, Zhao H., Shi Y., Cao Y., Yang D., Li Z. et al. Genome-wide association study identifies eightnew risk loci for polycystic ovary syndrome. Nat. Genet. 2012; 44(9): 1020-5. doi: 10.1038/ng.2384.
  36. Capalbo A., Sagnella F., Ара R., Fulghesu A.M., Lanzone A., Morciano A. et al. The 312N variant of the luteinizing hormone/choriogonadotropin receptor gene (LHCGR) confers up to 2 7-fold increased risk of polycystic ovary syndrome in a Sardinian population. Clin. Endocrinol. (Oxford). 2012; 77(1): 113-9.
  37. Wang P, Zhao H., Li T., Zhang W., Wu K., Li M. et al. Hypomethylation of the LH/choriogonadotropin receptor promoter region is a potential mechanism underlying susceptibility to polycystic ovary syndrome. Endocrinology. 2014; 155(4): 1445-52.
  38. Lazaros L., Hatzi E., Xita N., Takenaka A., Sofikitis N., Zikopoulos K., Georgiou I. Influence of FSHR diplotypes on ovarian response to standard gonadotropin stimulation for IVF/ICSI. J. Reprod. Med. 2013; 58(9-10): 395-401.
  39. Sun L., Peng Y, Sharrow A.C., Iqbal J., Zhang Z., Papachristou DJ. et al. FSH directly regulates bone mass. Cell. 2006; 125(2): 247-60.
  40. Marat A.L., Dokainish H., McPherson P.S. DENN domain proteins: regulators of Rab GTPases. J. Biol. Chem. 2011; 286(16): 13791-800.
  41. Del Villar K, Miller C.A. Down-regulation of DENN/MADD, a TNF receptor binding protein, correlates with neuronal cell death in Alzheimer’s disease brain and hippocampal neurons. Proc. Natl. Acad. Sci. USA. 2004; 101(12): 4210-5.
  42. Kawamura K, Cheng Y, Suzuki N., Deguchi M., Sato Y., Takae 5. et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc. Natl. Acad. Sci. USA. 2013; 110(43): 17474-9. doi: 10.1073/ pnas. 1312830110.
  43. Goodarzi M.O., Jones M.R., Li X., Chua A.K., Garcia O.A., Chen Y.D. et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J. Med. Genet. 2012; 49(2): 90-5.
  44. Louwers Y. V., Stolk L., Uitterlinden A.G. Replication of Chinese PCOS susceptibility loci in patients diagnosed with PCOS from Caucasian descent. In: Poster presented at: 95th Annual Meeting of the Endocrine Society. June 15-18, 2013, San Francisco, CA. Poster MON-549.
  45. Goodarzi M.O., Jones M.R., Li X, Chua A.K., Garcia O.A., Chen Y.D. et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J. Med. Genet. 2012; 49(2): 90-5. doi: 10.1136/jmedgenet-2011-100427.
  46. Welt C.K, Styrkarsdottir U., Ehrmann D.A., Thorleifsson G., Arason G., Gudmundsson J.A. et al. Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. J. Clin. Endocrinol. Metab. 2012; 97(7): E1342-7.
  47. Louwers Y.V., Stolk L., Uitterlinden A.G., Laven J.S. Cross-ethnic metaanalysis of genetic variants for polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2013; 98(12): E2006-12.
  48. BrowerM.A.JJonesM.R.)RotterJ.I.)KraussR.M.,LegroR.S.,AzgizR-,GoodarziM.O. Further investigation in europeans of susceptibility variants for olycystic ovary syndrome discovered in genome-wide association studies of Chinese individuals. J. Clin. Endocrinol. Metab. 2015; 100(1): E182-6. doi: 10.1210/jc.2014-2689.
  49. Cui L., Zhao H, Zhang B., Qu Z, Liu J., Liang X. et al. Genotype-phenotype correlations of PCOS susceptibility SNPs identified by GWAS in a large cohort of Han Chinese women. Hum. Reprod. 2013; 28(2): 538-44.
  50. Cui L., Li G., Zhong W., Bian Y, Su S., Sheng Y. Polycystic ovary syndrome susceptibility single nucleotide polymorphisms in women with a single PCOS clinical feature. Hum. Reprod. 2015; 30(3): 732-6.
  51. McAllister J.M., Modi B., Miller B.A., Biegler J., Bruggeman R., Legro R.S., Strauss J.F. 3rd. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc. Natl. Acad. Sci. USA. 2014; 111(15): E1519-27. doi: 10.1073/pnas.l400574111.

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