Comparative Clinical Pathology

, Volume 21, Issue 6, pp 1689–1696 | Cite as

Allelic variants of insulin receptor substrate-1 gene in Egyptian women with polycystic ovary syndrome

  • Fatma A. Elmougy
  • Marianne F. Morgan
  • Dina F. Elgayar
  • Abeer M. Mohey
  • Heba N. Baz
  • Ahmed M. Ali
Original Article


The insulin receptor substrate gene-1 (IRS-1) polymorphisms have been incriminated in insulin resistance; a frequent finding in polycystic ovary syndrome (PCOS). The commonest polymorphism associated with insulin resistance is gly972arg. Another polymorphism is the ala512 pro. This study aimed at elucidating the association of the gly972arg and the ala512pro polymorphisms of the IRS-1 gene with PCOS in Egyptian females. We employed a case–control study. The two polymorphisms were analyzed in 62 PCOS Egyptian female patients and 43 age-matched controls using a PCR-RFLP strategy. Fasting insulin, plasma glucose, and testosterone were analyzed by routine analytical methods and calculation of the homeostasis model assessment (HOMA) and the quantitative sensitivity check index (QUICK I) were done based on the results of the fasting insulin and glucose. It was found that 6.5% of the PCOS cases showed the Gly972Arg genotype. The Gly972Arg in IRS-1 polymorphism was not associated with PCOS (p = 0.556). A positive association was found between the gly972arg and the HOMA quartiles (p = 0.01). PCOS patients with the 972gly/arg genotype had higher glucose (p = 0.040), insulin (0.000), HOMA (0.000), and lower QUICK I (0.023) than PCOS with wild 972arg/arg genotype. Patients of PCOS with the 972gly/arg genotype were more insulin resistant than other patients with the wild genotype. Neither the patients nor the controls showed the mutant ala512pro genotype. Screening for gly972arg genotype can be based on the HOMA quartile ranking. The ala512pro genotype was not found in studied Egyptian women.


PCOS Insulin resistance gly972arg Polymorphism ala512pro Polymorphism 


Conflict of interest



  1. Almind K, Inoue G, Pedersen O, Kahn CR (1996) A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling: evidence from transfection studies. J Clin Investig 97:2569–2575PubMedCrossRefGoogle Scholar
  2. American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33:S62–S69CrossRefGoogle Scholar
  3. Archer J, Chang RJ (2004) Hirsutism and acne in polycystic ovary syndrome. Best Pract Res Clin Obstet Gynecol 18:737–754CrossRefGoogle Scholar
  4. Baba T, Endo T, Sata F, Honnma H, Kitajima Y, Hayashi T, Manase K, Kanaya M, Yamada H, Minakami H, Kishi R, Saito T (2007) Polycystic ovary syndrome is associated with genetic polymorphism in the insulin signaling gene IRS-1 but not ENPP1 in a Japanese population. Life Sci 81:850–854PubMedCrossRefGoogle Scholar
  5. Bayram F, Muderris LL, Guven M, Kelestimur F (2002) Comparison of high-dose finasteride (5 mg/day) versus low-dose finasteride (2.5 mg/day) in the treatment of hirsutism. Eur J Endocrinol 147:467–471PubMedCrossRefGoogle Scholar
  6. Bhattacharya SM (2009) Polycystic ovary syndrome and abnormalities in glucose tolerance. Int J Gynecol Obstet 105:29CrossRefGoogle Scholar
  7. Celi FS, Negri C, Tanner K, Raben N, De Pablo F, Rovira A, Pallardo LF, Martin-Vaquero P, Stern MP, Mitchell BD, Shuldiner AR (2000) Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Mexican Americans with type 2 diabetes mellitus. Diabetes Metab Res Rev 16:370–377PubMedCrossRefGoogle Scholar
  8. Clark PM (1999) Assay of insulin, proinsulin and c-peptide. Ann Clin Biochem 36(5):541–564, 2003PubMedGoogle Scholar
  9. Conway GC, Avey G, Rumsby C (1994) The tyrosine kinase domain of the insulin receptor gene is normal in women with hyperinsulinaemia and polycystic ovary syndrome. Hum Reprod 9:1861–1883Google Scholar
  10. Diamanti-Kandarakis E, Kouli CR, Bergiele AT (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
  11. Dilek S, Ertunc D, Tok EC, Erdal EM, Aktas A (2005) Association of Gly972Arg variant of insulin receptor substrate-1 with metabolic features in women with polycystic ovary syndrome. Fertil Steril 84:407–412PubMedCrossRefGoogle Scholar
  12. Dravecká I, Lazúrová I, Habalová V (2010) The prevalence of Gly972Arg and C825T polymorphisms in Slovak women with polycystic ovary syndrome and their relation to the metabolic syndrome. Gynecol Endocrinol 26(5):356–360PubMedCrossRefGoogle Scholar
  13. El Mkadem SA, Lautier C, Macari F (2001) Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to severe insulin resistance of women with polycystic ovary syndrome. Diabetes 50:2164–2168PubMedCrossRefGoogle Scholar
  14. Esposito DL, Li Y, Vanni C, Mammarella S, Veschi S, Della Loggia F, Mariani-Costantini R, Battista R, Quon P, Cama MJ (2003) A novel T608R missense mutation in insulin receptor substrate-1 identified in a subject with type 2 diabetes impairs metabolic insulin signaling. J Clin Endocrinol Metab 88:1468–1475PubMedCrossRefGoogle Scholar
  15. Ferriman DM, Gallwey JD (1961) Clinical assessment of body hair growth in women. J Clin Endocrinol 21:1440–1447CrossRefGoogle Scholar
  16. Happ MH, Machicao F, Stefan N, Thamer C, Tschritter O, Schnuck F, Wallwiener D, Strumvoll M, Haring HU, Frische A (2005) Genetic determination of insulin action in polycystic ovary syndrome. Exp Clin Endocrinol Diabetes 113:275–281CrossRefGoogle Scholar
  17. Jellma A, Zeegers MPA, Feskens EJM, Dagnelie PC, Mensink RP (2003) Gly972Arg variant in the insulin receptor substrate-1 gene and association with type 2 diabetes: a meta-analysis of 27 studies. Diabetologia 46:990–995CrossRefGoogle Scholar
  18. Jiang B, Kenna HA, Rasgon NL (2009) Genetic overlap between polycystic ovary syndrome and bipolar disorder: the endophenotype hypothesis. Med Hypothese 73:996–1004CrossRefGoogle Scholar
  19. Kane J, Middle J, Cowood M (2007) Measurment of serum testosterone in women. What should we do? Clin Biochem 44:5–15CrossRefGoogle Scholar
  20. Kazerooni T, Ghaffarpasand F, Kazerooni Y, Kazerooni M, Setoodeh S (2009) Short-term metformin treatment for clomiphene citrate-resistant women with polycystic ovary syndrome. Int J Gynecol Obstet 107:50–53CrossRefGoogle Scholar
  21. Keskin M, Kurtglu S, Kendirci M, Atabek ME, Yazici C (2005) Homeostasis model assessment is more reliable than the fasting glucose/insulin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescencts. Pediatrics 115:500–503CrossRefGoogle Scholar
  22. Knapp RG, Miller MC (1992) Describing the performance of a diagnostic test. Clinical epidemiology and biostatistics. Williams & Wilkins, Baltimore, p 42Google Scholar
  23. Lin TC, Yen JM, Gong KB, Kuo TC, Ku DC, Liang SF, Wu MJ (2006) Abnormal glucose tolerance and insulin resistance in polycystic ovary syndrome amongst the Taiwanese population—not correlated with insulin receptor substrate-1 Gly972Arg/Ala512Pro polymorphism. BMC Med Genet 7:7–36CrossRefGoogle Scholar
  24. Loannidis A, Ikaonomi E, Dimou N, Douma L, Bagos P (2010) Polymorphisms of the insulin receptor and the insulin receptor substrate genes on polycystic ovary syndrome: a Mendelian randomization meta-analysis. Mol Genet Metab 99(2):174–183CrossRefGoogle Scholar
  25. Ozdemir S, Ozdemir M, Görkemli H, Kiyici A, Bodur S (2010) Specific dermatologic features of the polycystic ovary syndrome and its association with biochemical markers of the metabolic syndrome and hyperandrogenism. Acta Obstet Gynecol Scand 89(2):199–204PubMedCrossRefGoogle Scholar
  26. Pappalardo MA, Russo GT, Pedone A, Pizzo A, Borrielli I, Stabile G, Artenisio AC, Amato A, Calvani M, Cucinotta D, Trimarchi F, Benvenga S (2010) Very high frequency of the polymorphism for the insulin receptor substrate 1 (IRS-1) at codon 972 (glycine972arginine) in Southern Italian women with polycystic ovary syndrome. Horm Metab Res 42(8):575–584PubMedCrossRefGoogle Scholar
  27. Quon MJ (2001) Limitation of the fasting glucose to insulin ratio as an index of insulin sensitivity. J Clin Endocrinol Metab 85:4615–4617CrossRefGoogle Scholar
  28. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2003) Revised consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 19(1):41–47CrossRefGoogle Scholar
  29. Shimokawa K, Kadowaki H, Sakura H, Otabe S, Hagura R, Kosaka K, Yazaki Y, Akanuma Y, Kadowaki T (1994) Molecular scanning of the glycogen synthase and insulin receptor substrate-1 genes in Japanese subjects with non-insulin-dependent diabetes mellitus. Biochem Biophys Res Commun 202(1):463–469PubMedCrossRefGoogle Scholar
  30. Sir-Petermann T, Pâerez-Bravo F, Angel B, Maliqueo M, Calvillan M, Palmino A (2001) C972R polymorphism of IRS 1 gene in women with polycystic ovary syndrome. Diabetologia 44:1200–1201PubMedCrossRefGoogle Scholar
  31. Sir-Petermann T, Angel B, Maliqueo M, Santos JL, Riesco MV, Toloza H, Pérez-Bravo F (2004) Insulin secretion in women who have polycystic ovary syndrome and carry the Gly972Arg variant of insulin receptor substrate-1 in response to a high-glycemic or low-glycemic carbohydrate load. Nutrition 20(10):905–910PubMedCrossRefGoogle Scholar
  32. Talbot J, Bicknell E, Rajkhowa M, Krook A, O’Rahilly S, Clayton R (1996) Molecular scanning of the insulin receptor gene in women with polycystic ovary syndrome. J Clin Endocrinol Metab 81(5):1979–1983PubMedCrossRefGoogle Scholar
  33. Trinder P (1969) Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem 6:24–27Google Scholar
  34. Trowsdale J (1993) Genomic structure and function in the MHC. Trends Genet 9:117–122PubMedCrossRefGoogle Scholar
  35. Valdés P, Cerda C, Barrene Chea M, Kehr C, Soto SP, Salazar LA (2008) No association between common Gly972Arg variant of the insulin receptor substrate-1 and polycystic ovary syndrome in Southern Chilean women. Clin Chem Acta 390:63–66CrossRefGoogle Scholar
  36. Villuendas G, Botella-Carretero J, Roldan B, Sancho J, Escobar-Morreale H, San Millan JL (2005) Polymorphisms in the insulin receptor substrate-1 (IRS-1) gene and the insulin receptor substrate-2 (IRS-2) gene influence glucose homeostasis and body mass index in women with polycystic ovary syndrome and non-hyperandrogenic controls. Hum Reprod 20:3184–3191PubMedCrossRefGoogle Scholar
  37. World Medical Association (2008) Declaration of Helsinki. Ethical principles for medical research involving human subjects, the 59th WMA General Assembly, Seoul, South KoreaGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2011

Authors and Affiliations

  • Fatma A. Elmougy
    • 1
  • Marianne F. Morgan
    • 1
  • Dina F. Elgayar
    • 1
    • 3
  • Abeer M. Mohey
    • 1
  • Heba N. Baz
    • 1
  • Ahmed M. Ali
    • 2
  1. 1.Department of Clinical and Chemical Pathology, Faculty of MedicineCairo UniversityGizaEgypt
  2. 2.Department of Obstetric and Gynecology, Faculty of MedicineCairo UniversityGizaEgypt
  3. 3.GizaEgypt

Personalised recommendations