Original Articles

The TNF-α-308G/A Gene Polymorphism and Serum TNF-α Levels in Women With Preeclampsia

Abstract

Objective: Worldwide, preeclampsia (PE) is a multifactorial disorder reported in 2–5% of pregnancies, which increases mortality during pregnancy. In general, 10–15% of maternal deaths are directly related to PE and eclampsia. One of the susceptibility genes for PE is tumor necrosis factor-α (TNF-α) expressed by most immune cells. TNF-α is a protein involved in various biological processes, including proliferation and apoptosis, as well as the expression of inflammatory genes. The goal of this study was to investigate the role of TNF-α single nucleotide polymorphism (SNP) -308G/A (rs1800629) and their relationship with TNF-α in PE patients.
Materials and methods: The SNP was genotyped in 90 cases and 90 controls. Whole blood was collected from women with PE and normal pregnancy in EDTA containing tubes, and DNA extraction was performed from their blood lymphocytes according to a standard phenol-chloroform procedure. Then, DNA was genotyped by real-time PCR and the polymorphism was detected by TaqMan assay. Serum levels of TNF-α protein were measured by enzyme-linked immunosorbent (ELISA) assay.
Results: TNF-α levels in women with PE were significantly higher than in healthy ones (p<0.001). We did not observe any correlation between allelic outbreak (p=0.3) and TNF-α-308G/A polymorphism (p=0.7) with the incidence of PE.
Conclusion: Although TNF-α-308G/A gene polymorphism does not appear to affect susceptibility to PE, an increased level of serum TNF-α can be used as a predictor for PE during pregnancy. We recommend that more research be conducted on possible factors related to the incidence of PE

1. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005; 308: 1592-4.
2. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009; 33: 130-7.
3. Mihu D, Razvan C, Malutan A, Mihaela C. Evaluation of maternal systemic inflammatory response in preeclampsia. Taiwan J Obstet Gynecol 2015; 54: 160-6.
4. Jonsson Y, Rubèr M, Matthiesen L, Berg G, Nieminen K, Sharma S, et al. Cytokine mapping of sera from women with preeclampsia and normal pregnancies.
J Reprod Immunol 2006; 70: 83-91.
5. Stonek F, Hafner E, Metzenbauer M, Katharina S, Stümpflen I, Schneeberger C, et al. Absence of an association of tumor necrosis factor (TNF)-alpha G308A, interleukin-6 (IL-6) G174C and interleukin-10 (IL-10) G1082A polymorphism in women with preeclampsia. Journal of reproductive immunology 2008; 77: 85-90.
6. Borzychowski AM, Sargent IL, Redman CW. Inflammation and pre-eclampsia. Semin Fetal Neonatal Med 2006; 11: 309-16.
7. Roberts JM, Gammill HS. Preeclampsia: recent insights. Hypertension 2005; 46: 1243-9.
8. Emi Aikawa N, de Carvalho JF, Artur Almeida Silva C, Bonfá E. Immunogenicity of Anti-TNF-alpha agents in autoimmune diseases. Clin Rev Allergy Immunol 2010; 38: 82-9.
9. Monzón-Bordonaba F, Vadillo-Ortega F, Feinberg RF. Modulation of trophoblast function by tumor necrosis factor-α: a role in pregnancy establishment and maintenance? Am J Obstet Gynecol 2002; 187: 1574-80.
10. Sharma A, Satyam A, Sharma JB. Leptin, IL-10 and inflammatory markers (TNF-alpha, IL-6 and IL-8) in pre-eclamptic, normotensive pregnant and healthy non-pregnant women. Am J Reprod Immunol 2007; 58: 21-30.
11. Kwak-Kim JYH, Gilman-Sachs A, Kim CE. T helper 1 and 2 immune responses in relationship to pregnancy, nonpregnancy, recurrent spontaneous abortions and infertility of repeated implantation failures. Chem Immunol Allergy 2005; 88: 64-79.
12. Eggert-Kruse W, Kiefer I, Beck C, Demirakca T, Strowitzki T. Role for tumor necrosis factor alpha (TNF-α) and interleukin 1-beta (IL-1β) determination in seminal plasma during infertility investigation. Fertil Steril 2007; 87: 810-23.
13. Ghareeb D, Abdelazem AS, Hussein EM, Al-Karamany AS. Association of TNF-α-308 G> A (rs1800629) polymorphism with susceptibility of metabolic syndrome. J Diabetes Metab Disord 2021; 20: 209- 15.
14. Mărginean CO, Mărginean C, Iancu M, Moldovan VG, Melit LE, Bănescu C. The impact of TNF-α 308G> A gene polymorphism on children’s overweight risk and an assessment of biochemical variables: A cross-sectional single-center experience. Pediatr Neonatol 2019; 60: 19-27.
15. Singh S, Sharma A, Arora SK. High producer haplotype (CAG) of-863C/A,-308G/A and-238G/A polymorphisms in the promoter region of TNF-α gene associate with enhanced apoptosis of lymphocytes in HIV-1 subtype C infected individuals from North India. PLoS One 2014; 9: e98020.
16. Umapathy D, Krishnamoorthy E, Mariappanadar V, Viswanathan V, Ramkumar KM. Increased levels of circulating (TNF-α) is associated with (-308G/A) promoter polymorphism of TNF-α gene in Diabetic Nephropathy. Int J Biol Macromol 2018; 107: 2113-21.
17. Saarela T, Hiltunen M, Helisalmi S, Heinonen S, Laakso M. Tumour necrosis factor-α gene haplotype is associated with pre-eclampsia. Mol Hum Reprod 2005; 11: 437-40.
18. Molvarec A, Jermendy Á, Nagy B, Kovács M, Várkonyi T, Hupuczi P, et al. Association between tumor necrosis factor (TNF)-α G-308A gene polymorphism and preeclampsia complicated by severe fetal growth restriction. Clin Chim Acta 2008; 392: 52-7.
19. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000; 183: S1-22.
20. Zargar M, Razi T, Ghanbarnejad M, Hemadi M. A prospective study of evaluation of changes in Biochemical and Urine parameters in Preeclampsia. International Journal of Biological Chemistry 2012; 6: 122-9.
21. Yie SM, Li LH, Xiao R, Librach CL. A single base-pair mutation in the 3'-untranslated region of HLA-G mRNA is associated with pre-eclampsia. Mol Hum Reprod 2008; 14: 649-53.
22. Darmochwal-Kolarz D, Kolarz B, Rolinski J, Leszczynska-Gorzelak B, Oleszczuk JJFhec. The concentrations of soluble HLA-G protein are elevated during mid-gestation and decreased in pre-eclampsia. Folia Histochem Cytobiol 2012; 50: 286-91.
23. Xu XW, Lu MH, Tan DM. Association between tumour necrosis factor gene polymorphisms and the clinical types of patients with chronic hepatitis B virus infection. Clin Microbiol Infect 2005; 11: 52-6.
24. Sharma A, Satyam A, Sharma JB. Leptin, IL‐10 and inflammatory markers (TNF‐α, IL‐6 and IL‐8) in pre‐eclamptic, normotensive pregnant and healthy non‐pregnant women. Am J Reprod Immunol 2007; 58: 21-30.
25. Morange PE, Tregouet DA, Godefroy T, Saut N, Bickel C, Rupprecht HJ, Lackner K, Barbaux S, Poirier O, Peiretti F, Nalbone G, Juhan-Vague I, Blankenberg S, Tiret L. Polymorphisms of the tumor necrosis factor-alpha (TNF) and the TNF-alpha converting enzyme (TACE/ADAM17) genes in relation to cardiovascular mortality: the AtheroGene study. J Mol Med (Berl) 2008; 86: 1153-61.
26. Mirhafez SR, Avan A, Pasdar A, Kazemi E, Ghasemi F, Tajbakhsh A, et al. Association of tumor necrosis factor-α promoter G-308A gene polymorphism with increased triglyceride level of subjects with metabolic syndrome. Gene 2015; 568: 81-4.
27. Gupta V, Gupta A, Jafar T, Gupta V, Agrawal S, Srivastava N, et al. Association of TNF-α promoter gene G-308A polymorphism with metabolic syndrome, insulin resistance, serum TNF-α and leptin levels in Indian adult women. Cytokine 2012; 57: 32-6.
28. Sesti LF, Crispim D, Canani LH, Polina ER, Rheinheimer J, Carvalho PS, et al. The− 308G> a polymorphism of the TNF gene is associated with proliferative diabetic retinopathy in Caucasian Brazilians with type 2 diabetes. Invest Ophthalmol Vis Sci 2015; 56: 1184-90.
29. Aranda F, Peres Wingeyer SD, Schneeberger E, Valerio M, Saint Martin E, Dal Pra F, et al. The− 308 G/A polymorphism in the tumor necrosis factor‐α gene is not associated with development and progression of rheumatoid arthritis in A rgentinean patients. Int
J Rheum Dis 2016; 19: 476-81.
30. Pazarbasi A, Kasap M, Guzel AI, Kasap H, Onbasioglu M, Ozbakir B, et al. Polymorphisms in the tumor necrosis factor-alpha gene in Turkish women with pre-eclampsia and eclampsia. Acta Med Okayama 2007; 61: 153-60.
31. Saarela T, Hiltunen M, Helisalmi S, Heinonen S, Laakso MJMhr. Tumour necrosis factor-α gene haplotype is associated with pre-eclampsia. Mol Hum Reprod 2005; 11: 437-40.
32. Costin N, Blaga LD, Ciuchină S, POP RB. Implication of tumor necrosis factor-alpha in preeclampsia. Applied Medical Informatics 2008; 23: 11-8.
33. Pinheiro MB, Gomes KB, Ronda CR, Guimarães GG, Freitas LG, Teixeira-Carvalho A, et al. Severe preeclampsia: association of genes polymorphisms and maternal cytokines production in Brazilian population. Cytokine 2015; 71: 232-7.
34. Raguema N, Ben Ali Gannoun M, Zitouni H, Ben Letaifa D, Seda O, Mahjoub T, et al. Contribution of -1031T/C and -376G/A tumor necrosis factor alpha polymorphisms and haplotypes to preeclampsia risk in Tunisia (North Africa). J Reprod Immunol 2022; 149: 103461.
35. Mohajertehran F, Tavakkol Afshari J, Rezaieyazdi Z, Ghomian N. Association of single nucleotide polymorphisms in the human tumor necrosis factor-α and interleukin 1-β genes in patients with pre-eclampsia. Iran J Allergy Asthma Immunol 2012; 11: 224-9.
36. Chen YP, Pfab T, Slowinski T, Richter CM, Godes M, Hocher B. Impact of genetic variation of tumor necrosis factor-alpha on gestational hypertension. Chin Med J (Engl) 2006; 119: 719-24.
37. Wang L, Qu G, Wu W, Tang X, Sun Y. Association between tumor necrosis factor-α-308G/A gene polymorphism and susceptibility to pre-eclampsia: An updated meta-analysis. Cytokine 2018; 111: 278-86.
38. Mohammadpour-Gharehbagh A, Jahantigh D, Eskandari M, Eskandari F, Rezaei M, Moghaddam SZ, et al. The role of TNF-α and TLR4 polymorphisms in the placenta of pregnant women complicated by preeclampsia and in silico analysis. Int J Biol Macromol 2019; 134: 1205-15.
39. Zubor P, Dokus K, Zigo I, Skerenova M, Pullmann R, Danko J. TNF-α G308A gene polymorphism has an impact on renal function, microvascular permeability, organ involvement and severity of preeclampsia. Gynecol Obstet Invest 2014; 78: 150-61.
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IssueVol 16, No 3 (September 2022) QRcode
SectionOriginal Articles
DOI https://doi.org/10.18502/jfrh.v16i3.10582
Keywords
Preeclampsia Tumor Necrosis Factor-alpha (TNF-α) Polymorphism Real-Time PCR Enzyme-Linked Immunosorbent Assay (ELISA)

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How to Cite
1.
Khodadadi A, Ghadiri A, Ghafourian M, Iranparast S, Najafian M. The TNF-α-308G/A Gene Polymorphism and Serum TNF-α Levels in Women With Preeclampsia. J Family Reprod Health. 2022;16(3):205-211.