AccScience Publishing / GPD / Online First / DOI: 10.36922/gpd.5204
Submit to GPD
Cite this article
12
Download
231
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
REVIEW ARTICLE

TNFA gene polymorphisms and the risk of endometriosis: An updated meta-analysis of genetic association studies

Amrit Sudershan1,2 ,  Showkat Malik3 ,  Srishty Sudershan4 ,  Agar Chander Pushap5 ,  Mohd Anis Ganaie3 ,  Irfan Ahmad Bhat3 ,  Feroze Ahmed Dar3 ,  Bashir Ahmad Sheikh3 ,  Mehraj Bashir3 ,  Showkat Ahmad Najar3 ,  Mohd Younis1,6 ,  Parvinder Kumar1,6*
Show Less
1 Institute of Human Genetics, University of Jammu, Jammu, Jammu and Kashmir, India
2 Department of Human Genetics, Sri Pratap College, Cluster University Srinagar, Kashmir, Jammu and Kashmir, India
3 Department of Zoology, Sri Pratap College, Cluster University Srinagar, Kashmir, Jammu and Kashmir, India
4 Department of Zoology, Central University Jammu, Samba, Jammu and Kashmir, India
5 Department of Education, Welcome to Dakshina Bharat Hindi Prachar Sabha, Madras, India
6 Department of Zoology, University of Jammu, Jammu, Jammu and Kashmir, India
GPD, 5204 https://doi.org/10.36922/gpd.5204
Submitted: 19 October 2024 | Revised: 2 January 2025 | Accepted: 9 January 2025 | Published: 24 January 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

The tumor necrosis factor-alpha (TNFA) gene plays a pivotal role in modulating inflammatory responses, and its variants have been hypothesized to influence susceptibility to endometriosis, a complex and multifactorial gynecological condition. Among the notable polymorphisms investigated are -238 G>A, -308 G>A, -850 C>T, -857 C>T, -863 C>A, and -1031 T>C. Despite substantial research, the evidence regarding their role as genetic risk factors for endometriosis remains inconclusive. To address this uncertainty, the present study conducted a systematic review of the literature to evaluate the association between TNFA variants and endometriosis risk. A comprehensive search of electronic databases was performed to identify relevant studies. Data extraction and quality assessment were carried out using the Newcastle-Ottawa Scale. Pooled odds ratios and 95% confidence intervals were calculated across various genetic models, with adjustments for multiple comparisons using the Bonferroni correction. Trial sequential analysis (TSA) was employed to determine the required sample size for conclusive results, and Egger’s test was used to assess publication bias. The analysis included 18 studies examining different TNFA polymorphisms, but no significant associations with endometriosis risk were identified. TSA revealed that the existing sample sizes were inadequate to detect definitive links. While the findings suggest that upstream variants of the TNFA gene are not associated with endometriosis risk, this does not conclusively rule out a role for TNFA in the disease pathogenesis. Further research involving larger, ethnically diverse populations is warranted to confirm these results and provide deeper insights into the genetic factors contributing to endometriosis.

 

Keywords
Endometriosis
Tumor necrosis factor-alpha
Endometriosis
Gene polymorphism
Funding
None.
Conflict of interest
The authors declare that they have no conflicts of interest.
References
  1. Smolarz B, Szyłło K, Romanowicz H. Endometriosis: Epidemiology, classification, pathogenesis, treatment and genetics (review of literature). Int J Mol Sci. 2021;22(19):10554. doi: 10.3390/ijms221910554

 

  1. Saunders PTK, Horne AW. Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell. 2021;184(11):2807-2824. doi: 10.1016/j.cell.2021.04.041

 

  1. Sudershan A, Sudershan S, Younis M, et al. Enlightening the association between TNF-α -308 G > A and migraine: A meta-analysis with meta-regression and trial sequential analysis. BMC Neurol 2023;23(1):159. doi: 10.1186/s12883-023-03174-x

 

  1. González-Ramos R, Van Langendonckt A, Defrère S, et al. Involvement of the nuclear factor-κB pathway in the pathogenesis of endometriosis. Fertil Steril. 2010;94(6): 1985-1994. doi: 10.1016/j.fertnstert.2010.01.013

 

  1. Laganà AS, Vitale SG, Salmeri FM, et al. Unus pro omnibus, omnes pro uno: A novel, evidence-based, unifying theory for the pathogenesis of endometriosis. Med Hypotheses. 2017;103:10-20. doi: 10.1016/j.mehy.2017.03.032

 

  1. D’Alfonso S, Richiardi PM. A polymorphic variation in a putative regulation box of the TNFA promoter region. Immunogenetics. 1994;39(2):150-154. doi: 10.1007/BF00188619

 

  1. Pizzo A, Salmeri FM, Ardita FV, et al. Behaviour of cytokine levels in serum and peritoneal fluid of women with endometriosis. Gynecol Obstet Invest. 2002;54(2):82-87. doi: 10.1159/000067717

 

  1. Xavier P, Belo L, Beires J, et al. Serum levels of VEGF and TNF-alpha and their association with C-reactive protein in patients with endometriosis. Arch Gynecol Obstet. 2006;273(4):227-231. doi: 10.1007/s00404-005-0080-4

 

  1. Malutan AM, Drugan T, Costin N, et al. Pro-inflammatory cytokines for evaluation of inflammatory status in endometriosis. Cent Eur J Immunol. 2015;40(1):96-102.

 

  1. Tarokh M, GhaffariNovin M, Poordast T, et al. Serum and peritoneal fluid cytokine profiles in infertile women with endometriosis. Iran J Immunol. 2019;16(2):151-162. doi: 10.22034/IJI.2019.80258

 

  1. Lee MK, Park AJ, Kim DH. Tumor necrosis factor-alpha and interleukin-6 promoter gene polymorphisms are not associated with an increased risk of endometriosis. Fertil Steril. 2002;77(6):1304-1305. doi: 10.1016/s0015-0282(02)03132-1

 

  1. Zhao ZZ, Nyholt DR, Le L, et al. Genetic variation in tumour necrosis factor and lymphotoxin is not associated with endometriosis in an Australian sample. Hum Reprod. 2007;22(9):2389-2397. doi: 10.1093/humrep/dem182

 

  1. Hsieh YY, Chang CC, Tsai FJ, et al. Polymorphisms for interleukin-4 (IL-4) -590 promoter, IL-4 intron3, and tumor necrosis factor alpha -308 promoter: Non-association with endometriosis. J Clin Lab Anal. 2002;16(3):121-126. doi: 10.1002/jcla.10021

 

  1. Rotman C, Fischel L, Cortez G, et al. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013;69(1):92-95. doi: 10.1111/aji.12034

 

  1. Lee GH, Choi YM, Kim SH, et al. Association of tumor necrosis factor-α gene polymorphisms with advanced stage endometriosis. Hum Reprod. 2008;23(4):977-981. doi: 10.1093/humrep/den016

 

  1. Kublinsky KS, Urazova OI, Novitsky VV, et al. Polymorphisms of cytokine genes in genital endometriosis. Neurosci Behav Physiol. 2019;49:962-971. doi: 10.1007/s11055-019-00825-w

 

  1. Wieser F, Fabjani G, Tempfer C, et al. Tumor necrosis factor-alpha promoter polymorphisms and endometriosis. J Soc Gynecol Investig. 2002;9(5):313-318. doi: 10.1016/s1071-5576(02)00174-0

 

  1. Chae SJ, Kim H, Jee BC, et al. Tumor necrosis factor (TNF)- TNF receptor gene polymorphisms and their serum levels in Korean women with endometriosis. Am J Reprod Immunol. 2008;60(5):432-439. doi: 10.1111/j.1600-0897.2008.00641.x

 

  1. Mao T, Zong LL, Wang YF, et al. Association of the tumor necrosis factor-alpha-1031T/C and its combination with interleukin-6-634C/G gene polymorphisms with susceptibility to endometriosis. Zhonghua Fuchanke Zazhi. 2012;47(5):328-332.

 

  1. Saliminejad K, Memariani T, Ardekani AM, et al. Association study of the TNF-α -1031T/C and VEGF +450G/C polymorphisms with susceptibility to endometriosis. Gynecol Endocrinol. 2013;29(11):974-977. doi: 10.3109/09513590.2013.824956

 

  1. Asghar T, Yoshida S, Kennedy S, et al. The tumor necrosis factor-alpha promoter -1031C polymorphism is associated with decreased risk of endometriosis in a Japanese population. Hum Reprod. 2004;19(11):2509-2514. doi: 10.1093/humrep/deh478

 

  1. Drakou A, Mavrogianni D, Ntzeros K, et al. 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

 

  1. Martorell-Marugan J, Toro-Dominguez D, Alarcon- Riquelme ME, Carmona-Saez P. MetaGenyo: A web tool for meta-analysis of genetic association studies. BMC Bioinformatics. 2017;18(1):563. doi: 10.1186/s12859-017-1990-4

 

  1. De Cassai A, Tassone M, Geraldini F, et al. Explanation of trial sequential analysis: Using a post-hoc analysis of meta-analyses published in Korean Journal of Anesthesiology. Korean J Anesthesiol. 2021;74(5):383-393. doi: 10.4097/kja.21218

 

  1. Sudershan A, Pushap AC, Kumar H, Kumar P. A comprehensive investigation into the association between MTHFR C677T, A1298C, and ACE I/D variants and risk of migraine: an updated meta-analysis of genetic association studies with trial sequential analysis and meta-regression. J Mol Neurosci. 2023;73(11-12):884-911. doi: 10.1007/s12031-023-02164-5

 

  1. 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):329-337. doi: 10.22074/ijfs.2015.4548

 

  1. Babaabasi B, Ahani A, Sadeghi F, Bashizade-Fakhar H, KhorramKhorshid HR. The association between TNF-alpha gene polymorphisms and endometriosis in an Iranian population. Int J Fertil Steril. 2019;13(1):6-11. doi: 10.22074/ijfs.2019.5542

 

  1. Mier-Cabrera J, Cruz-Orozco O, de la Jara-Díaz J, et al. Polymorphisms of TNF-alpha (-308), IL-1beta (+3954), and IL1-Ra (VNTR) are associated with severe stage of endometriosis in Mexican women: A case control study. BMC Womens Health. 2022;22(1):356. doi: 10.1186/s12905-022-01941-5

 

  1. Mardanian F, Aboutorabi R, Jefride Y, Amini G. Study of association between promoter tumor necrosis factor alpha gene polymorphisms in -850T/C, -863 A/C, and endometriosis. Adv Biomed Res. 2014;3:226. doi: 10.4103/2277-9175.145706

 

  1. Teramoto M, Kitawaki J, Koshiba H, et al. Genetic contribution of tumor necrosis factor (TNF)-alpha gene promoter (-1031, -863, and -857) and TNF receptor 2 gene polymorphisms in endometriosis susceptibility. Am J Reprod Immunol. 2004;51(5):352-357. doi: 10.1111/j.1600-0897.2004.00168.x

 

  1. Lakshmi KV, Shetty P, Vottam K, et al. Tumor necrosis factor alpha -C850T polymorphism is significantly associated with endometriosis in Asian Indian women. Fertil Steril. 2010;94(2):453-456. doi: 10.1016/j.fertnstert.2009.03.020

 

  1. Othman ER, Hornung D, Hussein M, et al. Soluble tumor necrosis factor-alpha receptors in the serum of endometriosis patients. Eur J Obstet Gynecol Reprod Biol. 2016;200:1-5. doi: 10.1016/j.ejogrb.2016.02.025

 

  1. Lyu J, Yang H, Lang J, Tan X. Tumor necrosis factor gene polymorphisms and endometriosis in Asians: A systematic review and meta-analysis. Chin Med J. 2014;127(9):1761-1767.

 

  1. Zhong S, Liang Y, Wu Z, Wei L. Association between polymorphisms of cytokine genes and endometriosis: A comprehensive systematic review and meta-analysis. J Reprod Immunol. 2023;158:103969. doi: 10.1016/j.jri.2023.103969

 

  1. Li J, Chen Y, Wei S, et al. Tumor necrosis factor and interleukin-6 gene polymorphisms and endometriosis risk in Asians: A systematic review and meta-analysis. Ann Hum Genet. 2014;78(2):104-116. doi: 10.1111/ahg.12048

 

  1. Cao XL, Chai J, Yu YY, et al. Association of TNF-α gene T-1031C polymorphism with endometriosis: A meta-analysis. Am J Reprod Immunol. 2020;84(6):e13305. doi: 10.1111/aji.13305

 

  1. Armstrong RA. When to use the Bonferroni correction. Ophthalmic Physiol Opt. 2014;34(5):502-508. doi: 10.1111/opo.12131

 

  1. Zhang RJ, Wild RA, Ojago JM. Effect of tumor necrosis factor-alpha on adhesion of human endometrial stromal cells to peritoneal mesothelial cells: An in vitro system. Fertil Steril. 1993;59(6):1196-1201. doi: 10.1016/s0015-0282(16)55976-7

 

  1. Braun DP, Ding J, Dmowski WP. Peritoneal fluid-mediated enhancement of eutopic and ectopic endometrial cell proliferation is dependent on tumor necrosis factor-alpha in women with endometriosis. Fertil Steril. 2002;78(4): 727-732. doi: 10.1016/s0015-0282(02)03318-6

 

  1. D’Hooghe TM, Nugent NP, Cuneo S, et al. Recombinant human TNFRSF1A (r-hTBP1) inhibits the development of endometriosis in baboons: A prospective, randomized, placebo- and drug-controlled study. Biol Reprod. 2006;74(1):131-136. doi: 10.1095/biolreprod.105.043349

 

  1. Falconer H, Mwenda JM, Chai DC, et al. Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon. Hum Reprod. 2006;21(7):1856-1862. doi: 10.1093/humrep/del044

 

  1. Sudershan A, Sudershan S, Sharma I, Kumar H, Panjaliya RK, Kumar P. Role of TNF-α in the pathogenesis of migraine. Pain Res Manag. 2024;2024:1377143. doi: 10.1155/2024/1377143

 

  1. Guo SW. Nuclear factor-kappaB (NF-kappaB): An unsuspected major culprit in the pathogenesis of endometriosis that is still at large? Gynecol Obstet Investig. 2007;63(2):71-97. doi: 10.1159/000096047

 

  1. Zdrojkowski Ł, Jasiński T, Ferreira-Dias G, Pawliński B, Domino M. The role of NF-κB in endometrial diseases in humans and animals: A review. Int J Mol Sci. 2023;24(3):2901. doi: 10.3390/ijms24032901

 

  1. Chen YJ, Wu HH, Liau WT, et al. A tumor necrosis factor-α inhibitor reduces the embryotoxic effects of endometriotic peritoneal fluid. Fertil Steril. 2013;100(5):1476-1485. doi: 10.1016/j.fertnstert.2013.07.1985
Share
Back to top
Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept