Volume 24, Issue 6 (Feb - Mar 2021)                   2021, 24(6): 486-497 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Sahmani M, Dabaghi Ghaleh T, Yargholi M, Foroghi F, Javadi A, Taherkhani K. Association Between the -1031 (T/C) Polymorphism of TNF-α Gene and Biochemical Factors in Women With Polycystic Ovary Syndrome. Journal of Inflammatory Diseases. 2021; 24 (6) :486-497
URL: http://journal.qums.ac.ir/article-1-3054-en.html
1- Department of Biochemistry, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.
2- Department of Obstetrics and Gynecology, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.
3- Department of Immunology, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran.
4- Department of Social Sciences, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran. , javadi_a@yahoo.com
5- Cellular and Molecular Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.
Full-Text [PDF 4013 kb]   (310 Downloads)     |   Abstract (HTML)  (1264 Views)
Full-Text:   (140 Views)
1. Introduction
olycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women and the most common cause of anovulatory infertility [1] followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations. Stage A 22-year-old woman reports having hirsutism and irregular menses. She describes unpredictable and infrequent menses (five or six per year. Its global prevalence is about %5–10% [2]. This syndrome is characterized by symptoms such as menstrual disorders (especially oligomenorrhea), presence of small cysts in the ovaries on ultrasound images, and the symptoms of hyperandrogenism such as hirsutism, acne, and hair loss [3, 4]. Although the exact cause of PCOS is still unknown, genetic factors can play an important role in the development of this disease. A number of studies have found some genetic factors associated with PCOS in different populations [876, 5, 4]. Tumor Necrosis Factor Alpha (TNF-α) is an adipokine that plays an important role in systemic inflammation. This inflammatory factor is produced by macrophages, mast cells, lymphocytes and epithelial cells. Moreover, TNF-α is involved in some biological activities such as cell proliferation and differentiation, induction of programmed cell death, cachexia, and tumor regression [9]. It is located in the short arm of chromosome 6 (6p21.2) and consists of 4 exons and 3 introns [9]. Several single-nucleotide polymorphisms have been identified in the promoter region of this gene, one of the most common of which is -1301 (T/C) polymorphism. Various studies have been performed on the effects of this polymorphism of TNF-α gene on some inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis and breast cancer [11121314] which has been considered as one of pathogenic factors for various diseases. The promoter -1031(T/C. In addition, previous studies have shown that this polymorphism plays an important role in the incidence of endometriosis and preeclampsia in Asian women [11, 15, 16] which has been considered as one of pathogenic factors for various diseases. The promoter -1031(T/C). Given the important role of this polymorphism in the incidence of various diseases, including gynecological diseases, the present study aims to, for the first time, investigate the relationship of this polymorphism and biochemical factors with a susceptibility to PCOS in Iranian women.
2. Materials and Methods
In this case-control study, 106 women with PCOS and 114 age-matched apparently healthy control women with normal menstrual cycles were recruited from the Reproductive Center of Kowsar Hospital in Qazvin, Iran. All patients met the diagnostic criteria for PCOS according to the 2003 Rotterdam ESHRE/ASRM PCOS consensus; i.e. the presence of at least two of the following criteria: oligo-ovulation and/or anovulation, clinical and/or biochemical hyperandrogenism, and polycystic ovaries on ultrasound images. Women with hypothyroidism, pregnancy, non-classical congenital adrenal hyperplasia, Cushing’s syndrome, and family history of diabetes were excluded from the study. For measuring biochemical parameters, 5 ml of blood was collected in two test tubes, one containing Ethylenediaminetetraacetic Acid (EDTA) used as anticoagulant for molecular tests and the other one without any anticoagulant for serum preparation. A DNA purification kit (QIAamp, Qiagen, USA) was used to isolate DNA from the blood leukocytes. For -1301 (T/C) genotype, a 251 bp fragment of DNA was amplified by using a DNA thermal cycler performing Polymerase Chain Reaction (PCR) by using oligonucleotide primers, including 5’-TATGTGATGGACTCACCAGG-3’ (Forward primer) and 5’-CCTCTACATGGCCCTGTCTT-3’ (Reverse primer). The PCR product was digested with Bbsi restriction enzyme. The fragments underwent electrophoresis by 2%–4% agarose gel and then stained with ethidium bromide. The quantitative data were expressed as Mean±Standard Deviation (SD). Chi-square test and logistic regression analysis were carried out to analyze the data. T-test was used to compare the mean values between the two groups. 
3. Results
The frequency of TT allele was 52.8% in the PCOS group and 41.2% in the control group. The frequency of TC allele was 26.4% in the PCOS group and 19.3% the control group. The frequency of CC allele was 20.8% in the PCOS group and 39.5% in the control group. Statistical test results showed a significant relationship between genotypic dispersion in TNF-α gene promoter resulting from -1301 (T/C) polymorphism of the two groups (P<0.01). Moreover, results showed that TT genotype was associated with an increased risk of PCOS (OR=2.43, P=0.006, 95%CI: 1.28-2.62). 
4. Discussion and Conclusion
The present study showed a relationship between -1301 (T/C) polymorphism of TNF-α gene and the risk of developing PCOS, such that with the increase of CC allele, the risk of PCOS decreases. PCOS is a polygenic pathological disorder that can affect several body organs [4, 7, 8]. Obesity and insulin resistance are associated with PCOS [4, 19]. Numerous studies have been performed on the association between the 1301 T/C polymorphism and diseases such as Behcet’s syndrome, Crohn’s disease and rheumatoid arthritis [11, 262728] which has been considered as one of pathogenic factors for various diseases. The promoter -1031(T/C. In patients with Behcet’s syndrome and Crohn’s disease, an increase in allele of -1301 (T/C) polymorphism has been reported compared to healthy people, while in patients with ulcerative colitis and hyperandrogenism, the frequency of this allele was lower than the in healthy people [11, 2829, 30]which has been considered as one of pathogenic factors for various diseases. The promoter -1031(T/C. In the present study, it was shown that the C allele can have a protective role in people with PCOS; This is consistent with the results of a previous study [11] which has been considered as one of pathogenic factors for various diseases. The promoter -1031(T/C). Our results showed a statistically significant difference between the mean serum triglyceride level, High-Density Lipoprotein (HDL), and the type of polymorphism in women with PCOS. Women with C allele of -1301 (T/C) polymorphism had lower serum triglyceride levels and higher HDL than other genetic groups. Since the increase in triglyceride level and decrease in HDL are important risk factors for obesity, insulin resistance and body mass index, it can be concluded that the change of these parameters in TT genotypes can play an effective role in development of PCOS in humans. In this study, patients with PCOS had a significant increase in testosterone and a decrease in Luteinizing Hormone (LH) compared to controls, which is consistent with the results of previous studies [431, 32]abnormalities in lipid profile and intrinsic inflammatory status are associated with disease progression. The purpose of this study was to evaluate the effect of the I405V polymorphism of cholesteryl ester transfer protein (CETP. Increased testosterone and decreased LH levels can be important risk factors for developing PCOS. Furthermore, despite significant differences in the levels of sex hormones such as testosterone and LH between PCOS and control groups, but, no difference was found between controls and PCOS patients who had -1301 (T/C) polymorphism of TNF-α gene.

Ethical Considerations
Compliance with ethical guidelines

The present study obtained its Ethical Approval from the Research Ethics Committee of Qazvin University of Medical Sciences (Code: IR.QUMS.REC.1396.7). In this study, the principles of ethics in medical research were considered according to the Helsinki Declaration and the National Ethics Committee in Medical Research. All patient information was kept confidential.

This study was extracted from the PhD. thesis of the third author at Department of Obstetrics and Gynecology, School of Medicine, Qazvin University of Medical Sciences, Qazvin.

Authors' contributions
Conceptualization: Mehdi Sahmani, Talaate Dabaghi Ghaleh, Farshad Foroghi; Writing, editing & review: Mehdi Sahmani, Maryam Yargholi, Amir Javadi; Methodology and data analysis: Amir Javadi; Laboratory tests: Farshad Foroghi, Khadijah Taherkhani; Project administration: Mehdi Sahmani, Talaate Dabaghi Ghaleh.

Conflict of interest
The authors declare no conflict of interest.

The authors would like to thank Ms. Zahra Rashvand, an expert from the reference laboratory.

  1. McCartney CR, Marshall JC. Clinical practice. Polycystic Ovary Syndrome. N Engl J Med. 2016; 375(1):54-64. [DOI:10.1056/NEJMcp1514916] [PMID] [PMCID]
  2. Yildiz BO, Bozdag G, Yapici Z, Esinler I, Yarali H. Prevalence, phenotype and cardiometabolic risk of polycystic ovary syndrome under different diagnostic criteria. Hum Reprod. 2012; 27(10):3067-73. [DOI:10.1093/humrep/des232] [PMID]
  3. Li S, Zhu D, Duan H, Tan Q. The epigenomics of polycystic ovarian syndrome: From pathogenesis to clinical manifestations. Gynecol Endocrinol. 2016; 32(12):942-6. [DOI:10.1080/09513590.2016.1203409] [PMID]
  4. Sahmani M, Dabbaghi Ghaleh T, Darabi M, Darabi M, Rashvand Z, Najafipour R. I405V polymorphism of CETP gene and lipid profile in women with endometriosis. Gynecol Endocrinol. 2013; 29(7):712-5. [DOI:10.3109/09513590.2013.797396] [PMID]
  5. Ajmal N, Khan SZ, Shaikh R. Polycystic Ovary Syndrome (PCOS) and genetic predisposition: A review article. Eur J Obstet Gynecol Reprod Biol X. 2019; 3:100060. [DOI:10.1016/j.eurox.2019.100060] [PMID] [PMCID]
  6. Franks S, McCarthy M. Genetics of ovarian disorders: Polycystic ovary syndrome. Rev Endocr Metab Disord. 2004; 5(1):69-76. [DOI:10.1023/B:REMD.0000016125.05878.96] [PMID]
  7. De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G, Petraglia F. Genetic, hormonal and metabolic aspects of PCOS: An update. Reprod Biol Endocrinol. 2016; 14(1):38. [DOI:10.1186/s12958-016-0173-x] [PMID] [PMCID]
  8. Joseph Sh, Barai RS, Bhujbalrao R, Idicula-Thomas S. PCOSKB: A KnowledgeBase on genes, diseases, ontology terms and biochemical pathways associated with PolyCystic Ovary Syndrome. Nucleic Acids Res. 2016; 44(D1):D1032-5. [DOI:10.1093/nar/gkv1146] [PMID] [PMCID]
  9. Willrich MA, Murray DL, Snyder MR. Tumor necrosis factor inhibitors: Clinical utility in autoimmune diseases. Transl Res. 2015; 165(2):270-82. [DOI:10.1016/j.trsl.2014.09.006] [PMID]
  10. Saha P, Smith A. TNF-α (Tumor Necrosis Factor-α). Arterioscler Thromb Vasc Biol. 2018; 38(11):2542-3. [DOI:10.1161/ATVBAHA.118.311660] [PMID]
  11. Yun JH, Choi JW, Lee KJ, Shin JS, Baek KH. The promoter -1031(T/C) polymorphism in tumor necrosis factor-alpha associated with polycystic ovary syndrome. Reprod Biol Endocrinol. 2011; 9:131. [DOI:10.1186/1477-7827-9-131] [PMID] [PMCID]
  12. Japur CC, Diez-Garcia RW, de Oliveira Penaforte FR, das Graças Pena G, de Araújo LB, de Sá MFS. Insulin, ghrelin and early return of hunger in women with obesity and polycystic ovary syndrome. Physiol Behav. 2019; 206:252-8. [DOI:10.1016/j.physbeh.2019.03.013] [PMID]
  13. Panidis D, Farmakiotis D, Koliakos G, Rousso D, Kourtis A, Katsikis I, et al. Comparative study of plasma ghrelin levels in women with polycystic ovary syndrome, in hyperandrogenic women and in normal controls. Hum Reprod. 2005; 20(8):2127-32. [DOI:10.1093/humrep/dei055] [PMID]
  14. Choi HJ, Cho YM, Moon MK, Choi HH, Shin HD, Jang HC, et al. Polymorphisms in the ghrelin gene are associated with serum high-density lipoprotein cholesterol level and not with type 2 diabetes mellitus in Koreans. J Clin Endocrinol Metab. 2006; 91(11):4657-63. [DOI:10.1210/jc.2005-2549] [PMID]
  15. Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev. 2016; 37(5):467-520. [DOI:10.1210/er.2015-1104] [PMID] [PMCID]
  16. Brynskov J, Foegh P, Pedersen G, Ellervik C, Kirkegaard T, Bingham A, et al. Tumour necrosis factor alpha converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease. Gut. 2002; 51(1):37-43. [DOI:10.1136/gut.51.1.37] [PMID] [PMCID]
  17. Zore T, Joshi NV, Lizneva D, Azziz R. Polycystic Ovarian Syndrome: Long-term health consequences. Semin Reprod Med. 2017; 35(3):271-81. [DOI:10.1055/s-0037-1603096] [PMID]
  18. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18(6):499-502. [DOI:10.1093/clinchem/18.6.499] [PMID]
  19. St-Pierre DH, Karelis AD, Coderre L, Malita F, Fontaine J, Mignault D, et al. Association of acylated and nonacylated ghrelin with insulin sensitivity in overweight and obese postmenopausal women. J Clin Endocrinol Metab. 2007; 92(1):264-9. [DOI:10.1210/jc.2006-1603] [PMID]
  20. Drakou A, Mavrogianni D, Ntzeros K, Protopapas A, Drakakis P, Loutradis D. Association between tumor necrosis factor-α gene-1031T/C promoter polymorphism and endometriosis in a European population. Horm Mol Biol Clin Investig. 2019; 40(2):20190033. [DOI:10.1515/hmbci-2019-0033] [PMID]
  21. Milner CR, Craig JE, Hussey ND, Norman RJ. No association between the -308 polymorphism in the Tumour Necrosis Factor alpha (TNFalpha) promoter region and polycystic ovaries. Mol Hum Reprod. 1999; 5(1):5-9. [DOI:10.1093/molehr/5.1.5] [PMID]
  22. Abutorabi R, Baradaran A, Sadat Mostafavi F, Zarrin Y, Mardanian F. Evaluation of tumor necrosis factor alpha polymorphism frequencies in endometriosis. Int J Fertil Steril. 2015; 9(3):329-37. [DOI:10.22074/ijfs.2015.4548] [PMID] [PMCID]
  23. Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016; 106(1):6-15. [DOI:10.1016/j.fertnstert.2016.05.003] [PMID]
  24. Kenigsberg LE, Agarwal C, Sin S, Shifteh K, Isasi CR, Crespi R, et al. Clinical utility of magnetic resonance imaging and ultrasonography for diagnosis of polycystic ovary syndrome in adolescent girls. Fertil Steril. 2015; 104(5):1302-9.e1-4. [DOI:10.1016/j.fertnstert.2015.08.002] [PMID] [PMCID]
  25. Taghavi SA, Bazarganipour F, Allan H, Khashavi Z, Reisi N, Dosha N, et al. Pelvic floor dysfunction and polycystic ovary syndrome. Hum Fertil. 2017; 20(4):262-7. [DOI:10.1080/14647273.2017.1292003] [PMID]
  26. Baptiste CG, Battista MC, Trottier A, Baillargeon JP. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol. 2010; 122(1-3):42-52. [DOI:10.1016/j.jsbmb.2009.12.010] [PMID] [PMCID]
  27. Joham AE, Palomba S, Hart R. Polycystic Ovary Syndrome, obesity, and pregnancy. Semin Reprod Med. 2016; 34(2):93-101. [DOI:10.1055/s-0035-1571195] [PMID]
  28. Ando T, Ichimaru Y, Konjiki F, Shoji M, Komaki G. Variations in the preproghrelin gene correlate with higher body mass index, fat mass, and body dissatisfaction in young Japanese women. Am J Clin Nutr. 2007; 86(1):25-32. [DOI:10.1093/ajcn/86.1.25] [PMID]
  29. Glueck CJ, Goldenberg N. Characteristics of obesity in polycystic ovary syndrome: Etiology, treatment, and genetics. Metabolism. 2019; 92:108-20. [DOI:10.1016/j.metabol.2018.11.002] [PMID]
  30. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015; 36(5):487-525. [DOI:10.1210/er.2015-1018] [PMID] [PMCID]
  31. Gu HF, Mou M, Liang ZG, Sun C, Ren XY, Xiao YB. The association between paraoxonase 1 gene polymorphisms and polycystic ovarian syndrome. Cell Mol Biol (Noisy-le-grand). 2016; 62(14):44-7. [PMID]
  32. Giandalia A, Pappalardo MA, Russo GT, Romeo EL, Alibrandi A, Di Bari F, et al. Influence of peroxisome proliferator-activated receptor-γ exon 2 and exon 6 and Insulin Receptor Substrate (IRS)-1 Gly972Arg polymorphisms on insulin resistance and beta-cell function in Southern Mediterranean women with polycystic ovary syndrome. J Clin Transl Endocrinol. 2018; 13:1-8. [DOI:10.1016/j.jcte.2018.05.002] [PMID] [PMCID]
Type of Study: Research | Subject: Biochemistry

Add your comments about this article : Your username or Email:

Send email to the article author

© 2021 CC BY-NC 4.0 | Journal of Inflammatory Diseases

Designed & Developed by : Yektaweb