Human Genetics

, Volume 129, Issue 5, pp 553–561 | Cite as

Common genetic variation in the 3′-untranslated region of gonadotropin-releasing hormone receptor regulates gene expression in cella and is associated with thyroid function, insulin secretion as well as insulin sensitivity in polycystic ovary syndrome patients

  • Qiaoli Li
  • Guizhong Yang
  • Ying Wang
  • Xiaoping Zhang
  • Qing Sang
  • Huan Wang
  • Xinzhi Zhao
  • Qinghe Xing
  • Lin He
  • Lei Wang
Original Investigation

Abstract

Gonadotropin-releasing hormone receptor (GNRHR) is a member of the G protein-coupled Ca(2+)-dependent family of receptors. It interacts with GnRH, whose signaling plays an important role in thyroid-stimulating hormone (TSH) secretion and insulin activity. There has been no study on the genetic effect of GNRHR on TSH secretion and insulin action in polycystic ovary syndrome (PCOS). We decided to investigate whether naturally occurring genetic variation at the human GNRHR locus is associated with thyroid function, insulin secretion and insulin sensitivity in PCOS. We undertook a systematic search for polymorphisms in GNRHR by resequencing the gene and then genotyped common single-nucleotide polymorphisms across the locus in 261 PCOS patients well-phenotyped for several metabolic traits to determine associations. A test for association of common genetic variants with susceptibility to PCOS was carried out in a large cohort of 948 subjects. Finally, we experimentally validated the marker-on-trait associations using GNRHR 3′-UTR region/reporter analysis in 293T cells. The 3′-UTR variant rs1038426 was associated with serum thyroid concentration (P = 0.007), change of insulin levels during oral glucose tolerance test (P = 0.004) and insulin sensitivity index (P = 0.014). In a functional study, 3′-UTR variant T allele increased reporter expression by a transfected luciferase reporter/GNRHR 3′-UTR expression plasmid. In conclusion, our results strongly suggest that common genetic variant in GNRHR contributes to the phenotypic expression of PCOS. The findings suggest novel pathophysiological links between the GNRHR locus and thyroid function and insulin secretion in PCOS.

Supplementary material

439_2011_954_MOESM1_ESM.doc (63 kb)
Supplementary material 1 (DOC 63 kb)

References

  1. Ansari MA, Dhar M, Spieker S, Bakht N, Rahman AM, Moore WV, Jacobson JD (2004) Modulation of diabetes with gonadotropin-releasing hormone antagonists in the nonobese mouse model of autoimmune diabetes. Endocrinology 145:337–342PubMedCrossRefGoogle Scholar
  2. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRefGoogle Scholar
  3. Bestetti GE, Barone D, Walz A, Moser B, Boujon CE, Brandli-Baiocco A, Rossi GL (1997) LHRH receptors and LHRH receptor-bearing cells in pituitaries of streptozocin diabetic male rats. Pharmacol Res 35:321–327PubMedCrossRefGoogle Scholar
  4. Carmina E, Azziz R (2006) Diagnosis, phenotype, and prevalence of polycystic ovary syndrome. Fertil Steril 86(Suppl 1):S7–S8PubMedCrossRefGoogle Scholar
  5. Chubb SA, Davis WA, Davis TM (2005) Interactions among thyroid function, insulin sensitivity, and serum lipid concentrations: the Fremantle diabetes study. J Clin Endocrinol Metab 90:5317–5320PubMedCrossRefGoogle Scholar
  6. Ciccone NA, Kaiser UB (2009) The biology of gonadotroph regulation. Curr Opin Endocrinol Diabetes Obes 16:321–327PubMedCrossRefGoogle Scholar
  7. Diamanti-Kandarakis E, Papavassiliou AG (2006) Molecular mechanisms of insulin resistance in polycystic ovary syndrome. Trends Mol Med 12:324–332PubMedCrossRefGoogle Scholar
  8. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, Filandra FA, Tsianateli TC, Spina GG, Zapanti ED, Bartzis MI (1999) A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 84:4006–4011PubMedCrossRefGoogle Scholar
  9. Dunaif A (1997) Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 18:774–800PubMedCrossRefGoogle Scholar
  10. Ehrmann DA (2005) Polycystic ovary syndrome. N Engl J Med 352:1223–1236PubMedCrossRefGoogle Scholar
  11. Faul F, Erdfelder E, Lang AG, Buchner A (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39:175–191PubMedCrossRefGoogle Scholar
  12. Greenwood TA, Rao F, Stridsberg M, Mahapatra NR, Mahata M, Lillie EO, Mahata SK, Taupenot L, Schork NJ, O’Connor DT (2006) Pleiotropic effects of novel trans-acting loci influencing human sympathochromaffin secretion. Physiol Genomics 25:470–479PubMedCrossRefGoogle Scholar
  13. Herrmann V, Buscher R, Go MM, Ring KM, Hofer JK, Kailasam MT, O’Connor DT, Parmer RJ, Insel PA (2000) Beta2-adrenergic receptor polymorphisms at codon 16, cardiovascular phenotypes and essential hypertension in whites and African Americans. Am J Hypertens 13:1021–1026PubMedCrossRefGoogle Scholar
  14. Klier M, Schusdziarra V, Pfeiffer EF (1980) Effect of luteinizing hormone-releasing hormone upon insulin release from rat islets in vitro. FEBS Lett 121:363–364PubMedCrossRefGoogle Scholar
  15. Li J, Burmeister M (2005) Genetical genomics: combining genetics with gene expression analysis. Hum Mol Genet 14(Spec No. 2):R163–R169Google Scholar
  16. Matsuda M, DeFronzo RA (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470PubMedCrossRefGoogle Scholar
  17. Michalaki MA, Vagenakis AG, Leonardou AS, Argentou MN, Habeos IG, Makri MG, Psyrogiannis AI, Kalfarentzos FE, Kyriazopoulou VE (2006) Thyroid function in humans with morbid obesity. Thyroid 16:73–78PubMedCrossRefGoogle Scholar
  18. Mueller A, Schofl C, Dittrich R, Cupisti S, Oppelt PG, Schild RL, Beckmann MW, Haberle L (2009) Thyroid-stimulating hormone is associated with insulin resistance independently of body mass index and age in women with polycystic ovary syndrome. Hum Reprod 24:2924–2930PubMedCrossRefGoogle Scholar
  19. Navratil AM, Song H, Hernandez JB, Cherrington BD, Santos SJ, Low JM, Do MH, Lawson MA (2009) Insulin augments gonadotropin-releasing hormone induction of translation in LbetaT2 cells. Mol Cell Endocrinol 311:47–54PubMedCrossRefGoogle Scholar
  20. Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769PubMedCrossRefGoogle Scholar
  21. O’Connor DT, Zhu G, Rao F, Taupenot L, Fung MM, Das M, Mahata SK, Mahata M, Wang L, Zhang K, Greenwood TA, Shih PA, Cockburn MG, Ziegler MG, Stridsberg M, Martin NG, Whitfield JB (2008) Heritability and genome-wide linkage in US and Australian twins identify novel genomic regions controlling chromogranin a: implications for secretion and blood pressure. Circulation 118:247–257PubMedCrossRefGoogle Scholar
  22. Okada R, Yamamoto K, Koda A, Ito Y, Hayashi H, Tanaka S, Hanaoka Y, Kikuyama S (2004) Development of radioimmunoassay for bullfrog thyroid-stimulating hormone (TSH): effects of hypothalamic releasing hormones on the release of TSH from the pituitary in vitro. Gen Comp Endocrinol 135:42–50PubMedCrossRefGoogle Scholar
  23. Okada R, Kobayashi T, Yamamoto K, Nakakura T, Tanaka S, Vaudry H, Kikuyama S (2009) Neuroendocrine regulation of thyroid-stimulating hormone secretion in amphibians. Ann N Y Acad Sci 1163:262–270PubMedCrossRefGoogle Scholar
  24. Palomba S, Russo T, Orio F Jr, Sammartino A, Sbano FM, Nappi C, Colao A, Mastrantonio P, Lombardi G, Zullo F (2004) Lipid, glucose and homocysteine metabolism in women treated with a GnRH agonist with or without raloxifene. Hum Reprod 19:415–421PubMedCrossRefGoogle Scholar
  25. Poppe K, Glinoer D (2003) Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 9:149–161PubMedCrossRefGoogle Scholar
  26. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25Google Scholar
  27. Simard M, Mirell CJ, Pekary AE, Drexler J, Kovacs K, Hershman JM (1988) Hormonal control of thyrotropin and growth hormone secretion in a human thyrotrope pituitary adenoma studied in vitro. Acta Endocrinol (Copenh) 119:283–290Google Scholar
  28. Smith MR, Lee H, Nathan DM (2006) Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 91:1305–1308PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Qiaoli Li
    • 1
    • 2
  • Guizhong Yang
    • 3
  • Ying Wang
    • 3
  • Xiaoping Zhang
    • 3
  • Qing Sang
    • 1
  • Huan Wang
    • 1
  • Xinzhi Zhao
    • 1
    • 2
  • Qinghe Xing
    • 1
    • 2
  • Lin He
    • 1
    • 2
  • Lei Wang
    • 1
    • 2
  1. 1.Institute of Biomedical ScienceFudan UniversityShanghaiPeople’s Republic of China
  2. 2.Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of EducationShanghai Jiao Tong UniversityShanghaiPeople’s Republic of China
  3. 3.Xi’an the fourth hospitalXi’an710069People’s Republic of China

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