Molecular Biology Reports

, Volume 46, Issue 6, pp 5821–5829 | Cite as

Analysis of VEGF gene polymorphisms and serum VEGF protein levels contribution in polycystic ovary syndrome of patients

  • Lei Bao
  • Rabbani Syed
  • Mustafa Sawsan AloahdEmail author
Original Article


Vascular endothelial growth factor (VEGF) is a well-known factor in reproductive function and contributes to the pathogenesis of polycystic ovary syndrome (PCOS). Genetic variations in VEGFA gene were suggested to contribute alterations in VEGF secretion and PCOS. This study evaluated the association of VEGFA SNPs with altered VEGF secretion level and PCOS among ethnically-matched control women. This prospective case–control study was conducted from 2016 to 2018 and comprised of 55 women with PCOS and 52 control subjects. ELISA was used to measure VEGF levels; and various other related bio chemicals whereas the genotyping of VEGFA variants was performed through the analysis of nine SNPs of VEGF. PRL, E2, PRGE testosterone and glucose level were found to be insignificantly different. The levels of FSH, LH, LH/FSH, TT, insulin, SHBG and HOMA-IR were significantly higher in the study group. Among the nine tested variants of VEGF SNPs, two SNPs rs3025020 and rs833061, consisted of TT (Recessive and Dominant homozygous, respectively) which were marginally higher in test. The SNP rs1570360 had significantly higher GG allele (32.73%) which was recessive homozygous. There was no significant difference observed in genotype frequencies related to higher value of VEGF. The genotype frequencies for the studied SNPs were in alignment with Hardy–Weinberg equilibrium (HWE). The mean serum VEGF levels got significantly increased in PCOS group. No significant association was found between VEGF genotypes and its serum levels. VEGF levels in rs699947 (AA-major homozygous), rs3025039 (CC-major homozygous) and rs833061 (TT & CC-major & minor homozygous) genotypes were significantly higher in PCOS. The study results evidently proved that the allelic variants in genes may be a factor for PCOS and VEGF serum levels with respect to few SNP variants only. These findings indicated that VEGF may be involved in PCOS status and confirmed the previous association between genetic variants in VEGF, serum level of VEGF protein and PCOS.


Vascular endothelial growth factor (VEGF) Polycystic ovary syndrome (PCOS) genetic variation Single nucleotide polymorphism Serum VEGF levels 


Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Informed consent

Written informed consent was obtained from the participants and in case of the minor study participant, informed consent was granted from the legally authorized representatives of the minors with the option to withdraw them from the study at any time.


  1. 1.
    Kaczmarek MM, Schams D, Ziecik AJ (2005) Role of vascular endothelial growth factor in ovarian physiology: an overview. Reprod Biol 5:111–136PubMedGoogle Scholar
  2. 2.
    Peitsidis P, Agrawal R (2010) Role of vascular endothelial growth factor in women with PCO and PCOS: a systemic review. Reprod Biomed Online 20:444–452PubMedGoogle Scholar
  3. 3.
    Ben Salem A, Attaoua R, Mtiraoui N, Meddeb S, Kacem O, Ajina M, Souissi M, Poucheret P, Normand C, Mahjoub T et al (2015) Haplotyping strategy highlights the specificity of FTO gene association with polycystic ovary syndrome in Tunisian women population. Gene 565:166–170PubMedGoogle Scholar
  4. 4.
    Özkan S, Vural B, Çalışkan E, Bodur H, Türköz E, Vural F (2007) Color Doppler sonographic analysis of uterine and ovarian artery blood flow in women with polycystic ovary syndrome. J Clin Ultrasound 35:305–313PubMedGoogle Scholar
  5. 5.
    Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO (2004) The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89:2745–2749PubMedGoogle Scholar
  6. 6.
    Norman RJ, Dewailly D, Legro RS, Hickey TE (2007) Polycystic ovary syndrome. Lancet 370:685697Google Scholar
  7. 7.
    Carmina E (2013) Obesity, adipokines and metabolic syndrome in polycystic ovary syndrome. Front Horm Res 40:40–50PubMedGoogle Scholar
  8. 8.
    Hurd WW, Abdel-Rahman MY, Ismail SA, Abdellah MA, Schmotzer CL, Sood A (2011) Comparison of diabetes mellitus and insulin resistance screening methods for women with polycystic ovary syndrome. Fertil Steril 96:1043–1047PubMedGoogle Scholar
  9. 9.
    Deligeoroglou E, Kouskouti C, Christopoulos P (2009) The role of genes in the polycystic ovary syndrome: predisposition and mechanisms. Gynecol Endocrinol 25:603–609PubMedGoogle Scholar
  10. 10.
    Victor VM, Rocha M, Banuls C, Sanchez-Serrano M, Sola E, Gomez M, Hernandez-Mijares A (2009) Mitochondrial complex I impairment in leukocytes from polycystic ovary syndrome patients with insulin resistance. J Clin Endocrinol Metab 94:3505–3512PubMedGoogle Scholar
  11. 11.
    Kashanian M, Fazy Z, Pirak A (2008) Evaluation of the relationship between gestational diabetes and a history of polycystic ovarian syndrome. Diabetes Res Clin Pract 80:289–292PubMedGoogle Scholar
  12. 12.
    Escobar-Morreale HF, Luque-Ramírez M, San Millán JL (2005) The molecular-genetic basis of functional hyperandrogenism and the polycystic ovary syndrome. Endocr Rev 26:251–282PubMedGoogle Scholar
  13. 13.
    Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI (2006) Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab 91:2100–2104PubMedGoogle Scholar
  14. 14.
    Lee SJ, Lee SY, Jeon HS, Park SH, Jang JS, Lee GY, Son JW, Kim CH, Lee WK, Kam S, Park RW (2005) Vascular endothelial growth factor gene polymorphisms and risk of primary lung cancer. Cancer Epidemiol Prev Biomark 14:571–575Google Scholar
  15. 15.
    Al-Habboubi HH, Sater MS, Almawi AW, Al-Khateeb GM, Almawi WY (2011) Contribution of VEGF polymorphisms to variation in VEGF serum levels in a healthy population. Eur Cytokine Netw 22:154–158PubMedGoogle Scholar
  16. 16.
    Ruggiero D, Dalmasso C, Nutile T, Sorice R, Dionisi L, Aversano M et al (2011) Genetics of VEGF serum variations in human isolated populations of Cilento: importance of VEGF polymorphisms. PLoS ONE 6:e16982PubMedPubMedCentralGoogle Scholar
  17. 17.
    Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, Flockhart DA, Hancock B, Davidson N, Gralow J, Dickler M (2008) Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26:4672PubMedPubMedCentralGoogle Scholar
  18. 18.
    Abd El Aal DE, Mohamed SA, Amine AF, Meki AR (2005) Vascular endothelial growth factor and insulin-like growth factor-1 in polycystic ovary syndrome and their relation to ovarian blood flow. Eur J Obstet Gynecol Reprod Biol 118:219–224PubMedGoogle Scholar
  19. 19.
    Agrawal R, Sladkevicius P, Engmann L, Conway GS, Payne NN, Bekis J et al (2008) Serum vascular endothelial growth factor concentrations and ovarian stromal blood flow are increased in women with polycystic ovaries. Hum Reprod 13:651–655Google Scholar
  20. 20.
    Artini PG, Ruggiero M, Parisen Toldin MR, Monteleone P, Monti M, Cela V et al (2009) Vascular endothelial growth factor and its soluble receptor in patients with polycystic ovary syndrome undergoing IVF. Hum Fertil 12:40–44Google Scholar
  21. 21.
    El Behery MM, Diab AE, Mowafy H, Ebrahiem MA, Shehata AE (2011) Effect of laparoscopic ovarian drilling on vascular endothelial growth factor and ovarian stromal blood flow using 3-dimensional power Doppler. Int J Gynecol Obstet 112:119–121Google Scholar
  22. 22.
    Andraweera PH, Dekker GA, Dissanayke VHW, Bianco-Miotto T, Jayasekara RW, Roberts CT (2013) Vascular endothelial growth factor family gene polymorphisms in preeclampsia in Sinhalese women in Sri Lanka. J Matern Fetal Med 26:532–536Google Scholar
  23. 23.
    Banyasz I, Szabo S, Bokodi G, Vannay A, Vasarhelyi B, Szabo A et al (2006) Genetic polymorphisms of vascular endothelial growth factor in severe pre-eclampsia. Mol Hum Reprod 12:233–236PubMedGoogle Scholar
  24. 24.
    Hefler LA, Mustea A, Konsgen D, Concin N, Tanner B, Strick R et al (2007) Vascular endothelial growth factor gene polymorphisms are associated with prognosis in ovarian cancer. Clin Cancer Res 13:898–901PubMedGoogle Scholar
  25. 25.
    Zidi S, Stayoussef M, Gazouani E, Mezlini A, Yacoubi-Loueslati B, Almawi WY (2015) Relationship of common vascular endothelial growth factor polymorphisms and haplotypes with the risk of cervical cancer in Tunisians. Cytokine 74:108–112PubMedGoogle Scholar
  26. 26.
    Almawi WY, Saldanha FL, Mahmoud NA, Al-Zaman I, Sater MS, Mustafa FE (2013) Relationship between VEGF polymorphisms and serum VEGF protein levels and recurrent spontaneous miscarriage. Hum Reprod 28:2628–2635PubMedGoogle Scholar
  27. 27.
    Li L, Donghong L, Shuguang W, Hongbo Z, Jing Z, Shengbin L (2013) Polymorphisms in the vascular endothelial growth factor gene associated with recurrent spontaneous miscarriage. J Matern Fetal Med 26:686–690Google Scholar
  28. 28.
    Paradowska-Gorycka A, Pawlik A, Romanowska-Prochnicka K, Haladyj E, Malinowski D, Stypinska B, Manczak M, Olesinska M (2016) Relationship between VEGF gene polymorphisms and serum VEGF protein levels in patients with rheumatoid arthritis. PLoS ONE 11(8):e0160769PubMedPubMedCentralGoogle Scholar
  29. 29.
    Consensus Workshop Group (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81(1):19–25Google Scholar
  30. 30.
    Patel SR, Korytkowski MT (2000) Polycystic ovary syndrome: how best to establish a diagnosis. Women Health Prim Care 3:55–69Google Scholar
  31. 31.
    Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS (2015) Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev 36:487–525PubMedPubMedCentralGoogle Scholar
  32. 32.
    Almawi WY, Gammoh E, Malalla ZH, Al-Madhi SA (2016) Analysis of VEGFA variants and changes in VEGF levels underscores the contribution of VEGF to polycystic ovary syndrome. PLoS ONE 11(11):e0165636PubMedPubMedCentralGoogle Scholar
  33. 33.
    Salem AB, Megdich F, Kacem O, Souayeh M, Ali FH, Hizem S, Janhai F, Ajina M, Abu-Elmagd M, Assidi M, Al Qahtani MH (2016) Vascular endothelial growth factor (VEGFA) gene variation in polycystic ovary syndrome in a Tunisian women population. BMC Genom 17(9):748Google Scholar
  34. 34.
    Chen Y, Fang SY (2018) Potential genetic polymorphisms predicting polycystic ovary syndrome. Endocr Connect 7(5):R187–R195PubMedPubMedCentralGoogle Scholar
  35. 35.
    Bhat A, Koul A, Sharma S, Rai E, Bukhari SI et al (2007) The possible role of 10398A and 16189C mtDNA variants in providing susceptibility to T2DM in two North Indian populations: a replicative study. Hum Genet 120:821–826PubMedGoogle Scholar
  36. 36.
    Liu CS, Cheng WL, Lee CF, Ma YS, Lin CY et al (2006) Alteration in the copy number of mitochondrial DNA in leukocytes of patients with mitochondrial encephalomyopathies. Acta Neurol Scand 113:334–341PubMedGoogle Scholar
  37. 37.
    Lee EJ, Oh B, Lee JYL, Kimm K, Park JM, Baek KH (2008) Association study between single nucleotide polymorphisms in the VEGF gene and polycystic ovary syndrome. Fertil Steril 89:1751–1759PubMedGoogle Scholar
  38. 38.
    Vural P, Kusku-Kiraz Z, Dogru-Abbasoglu S, Cil E, Karadag B, Akgul C et al (2009) Vascular endothelial growth factor -2578A/C, -460T/C and +405G/C polymorphisms in polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol 147:57–60PubMedGoogle Scholar
  39. 39.
    Guruvaiah P, Govatati S, Reddy TV, Lomada D, Deenadayal M, Shivaji S et al (2014) The VEGF +405G>C 5′ untranslated region polymorphism and risk of PCOS: a study in the South Indian women. J Assist Reprod Genet 31:1383–1389PubMedPubMedCentralGoogle Scholar
  40. 40.
    Agrawal R, Jacobs H, Payne N, Conway G (2002) Concentration of vascular endothelial growth factor released by cultured human luteinized granulose cells is higher in women with polycystic ovaries than in women with normal ovaries. Fertil Steril 78(6):1164–1169PubMedGoogle Scholar
  41. 41.
    Abd El Aal DE, Mohamed SA, Amine AF, Meki AR (2005) Vascular endothelial growth factor and insulin-like growth factor-1 in polycystic ovary syndrome and their relation to ovarian blood flow. Eur J Obstet Gynecol Reprod Biol 118(2):219–224PubMedGoogle Scholar
  42. 42.
    Artini PG, Monti M, Matteucci C, Valentino V, Cristello F, Genazzani AR (2006) Vascular endothelial growth factor and basic fibroblast growth factor in polycystic ovary syndrome during controlled ovarian hyperstimulation. Gynecol Endocrinol 22(8):465–470PubMedGoogle Scholar
  43. 43.
    Artini PG, Ruggiero M, Parisen Toldin MR, Monteleone P, Monti M, Cela V, Genazzani AR (2009) Vascular endothelial growth factor and its soluble receptor in patients with polycystic ovary syndrome undergoing IVF. Hum Fertil 12(1):40–44Google Scholar
  44. 44.
    Davies N (2016) PCOS: polycystic ovarian syndrome. Diabetes Self Manag 33(1):44–47PubMedGoogle Scholar
  45. 45.
    Nakajima K-I, Nakamura M, Ishisaki A, Kozakai T (2009) Synergistic effect of dexamethasone and prolactin on VEGF expression in bovine mammary epithelial cells via p44/p42 MAP kinase. Asian-Aust J Anim Sci 22(6):788–795Google Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.The International Peace Maternity and Child Health Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
  2. 2.Shanghai Key Laboratory of Embryo Original DiseasesShanghaiChina
  3. 3.Shanghai Municipal Key Clinical SpecialtyShanghaiChina
  4. 4.Department of Pharmaceutics, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  5. 5.College of Life ScienceMaulana Azad College of Arts and ScienceAurangabadIndia

Personalised recommendations