Biogenetic Markers for Predicting Response to Immunotherapy in Rheumatoid Arthritis Immunمخلغ
##plugins.themes.bootstrap3.article.main##
Background: TNF-α plays a critical role in the pathogenesis of RA. Gene polymorphisms occurring in this pro-inflammatory cytokine or their receptors may influence responses to biological therapy. Objectives: This study aimed to evaluate the impact of -238G/A(rs361525), -308G/A(rs1800629), -376G/A(rs1800750), +489G/A(rs80267059) SNPs in TNF-α and +587T/G(rs1061622), +884A/G(rs5746032) SNPs in TNFRII genes on responsiveness to TNF inhibitors as well as their effect on serum levels of TNF-α and TNFRII. Subjects and methods: Sixty patients with RA treated with anti-TNF therapy (30 responders and 30 non-responders) were allocated to this study. SNPs in the TNF-α and TNFRII genes were studied by three different techniques: PCR-sequencing, PCR-RFLP, and q-PCR-TaqMan assay. TNF-α and TNFRII serum levels were determined using the ELISA technique. Results: TNF-α -308 (GA), +489 (GA), and TNFRII +587 (TG) genotypes were found to be more associated with non-responsiveness to TNF than homozygous genotypes (OR: 1.3, 2.5, and 2.0, respectively). On other hand, TNF-α -238 and -376 (GA) genotypes, were found to be more associated with TNFi responsiveness than homozygous genotypes (OR: 0.172 and 0.22, respectively). However, none of them reached a significant level. Furthermore, the studied SNPs were found to be unrelated to serum levels of TNF-α and TNFRII. Conclusion: According to our findings, the TNF-α -238G/A, -308G/A, -376G/A, +489G/A, and TNFRII +587T/G, +884A/G SNPs were not significantly associated with the responsiveness of RA patients to biological therapy and had no effect on the serum levels of TNF-α and TNFR.
Downloads
Metrics
References
-
Lin Y-J, Anzaghe M, Schülke S. Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis. Cells [Internet]. 2020 Apr 3;9(4):880. Available from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226834/.
DOI | Google Scholar
1
-
Moelants EA, Mortier A, Van Damme J, Proost P. Regulation of TNF‐α with a focus on rheumatoid arthritis. Immuno & Cell Bio. 2013 Apr 30;91(6):393–401.
DOI | Google Scholar
2
-
Fragoso, J. M. Tumor necrosis factor alpha (TNF-α) in autoimmune diseases (AIDs): molecular biology and genetics. Gac Med de Mex.2014; 150(4), 334–344.
Google Scholar
3
-
Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: Pathological Mechanisms and Modern Pharmacologic Therapies. Bone Res. 2018 Apr 27;6(1).
DOI | Google Scholar
4
-
Mitoma H, Horiuchi T, Tsukamoto H, Ueda N. Molecular mechanisms of action of anti-TNF-α agents–Comparison among therapeutic TNF-α antagonists. Cyto [Internet]. 2018 Jan 1; 101:56–63. Available from:https://www.sciencedirect.com/science/article/pii/S1043466616304689.
DOI | Google Scholar
5
-
Rubbert-Roth A, Szabó MZ, Kedves M, Nagy G, Atzeni F, Sarzi-Puttini P. Failure of anti-TNF treatment in patients with rheumatoid arthritis: The pros and cons of the early use of alternative biological agents. Autoimmu Rev [Internet]. 2019 Dec 1 [cited 2021 Jan 18];18(12):102398. Available from: https://pubmed.ncbi.nlm.nih.gov/31639514/.
DOI | Google Scholar
6
-
Dedmon, L. E. The genetics of rheumatoid arthritis. Rheumatol.2020 Jul 8; 59(10), 2661–2670.
DOI | Google Scholar
7
-
Murdaca G, Gulli R, Spanò F, Lantieri F, Burlando M, Parodi A, et al. TNF-α gene polymorphisms: association with disease susceptibility and response to anti-tnf-α treatment in psoriatic arthritis. J of Inves Dermato [Internet]. 2014 Oct [cited 2020 Jan 8];134(10):2503–9. Available from: https://www.sciencedirect.com/science/article/pii/S0022202X15364939.
DOI | Google Scholar
8
-
Pavy S, Toonen EJM, Miceli-Richard C, Barrera P, van Riel PLCM, Criswell LA, et al. Tumour necrosis factor α −308G-A polymorphism is not associated with response to TNFα blockers in Caucasian patients with rheumatoid arthritis: systematic review and meta-analysis. Ann of the Rheum Dis. 2009 Dec 4;69(6):1022–8.
DOI | Google Scholar
9
-
Morales-Lara MJ, Cañete JD, Torres-Moreno D, Hernández MV, Pedrero F, Celis R, et al. Effects of polymorphisms in TRAILR1 and TNFR1A on the response to anti-TNF therapies in patients with rheumatoid and psoriatic arthritis. Joint Bone Sp. 2012 Dec;79(6):591–6.
DOI | Google Scholar
10
-
Mahmood, A., Al-Kazaz, A., Ad’hiah, A. A single nucleotide polymorphism of tumor necrosis factor alpha gene (rs1800629) is not associated with rheumatoid arthritis in a sample of Iraqi patients. J Gene Environ Res Con. 2017; 5(2), 59–63.
Google Scholar
11
-
Alanzy, A. K., Alta’ee, A. H., Alrubiae, S. J. Serum tumor necrosis factor alpha and gene polymorphisms in rheumatoid arthritis patients in Babylon Province, Iraq. J of Glo Pharma Technol. 2018; 10(3), 387–395.
Google Scholar
12
-
Alwaeli, A. Z., Albarqaawee, A. C., Alsalami, E. H. Joints’ changes in rheumatoid arthritis is reduced by polymorphism of TNF-A (-238 G/A-308 G/A) and IL-1β (+ 3953 C/T) in Najaf population. Eur J of BioSci. 2020; 14(2).
Google Scholar
13
-
Chen L, Huang Z, Liao Y, Yang B, Zhang J. Association between tumor necrosis factor polymorphisms and rheumatoid arthritis as well as systemic lupus erythematosus: a meta-analysis. Brazilian J of Med and Bio Res. 2019;52(3).
DOI | Google Scholar
14
-
Roda G, Jharap B, Neeraj N, Colombel J-F. Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clin and Trans Gastroentero. 2016 Jan;7(1): e135.
DOI | Google Scholar
15
-
Farhangian ME, Feldman SR. Immunogenicity of biologic treatments for psoriasis: therapeutic consequences and the potential value of concomitant methotrexate. Amer J of Clin Dermato. 2015 May 12;16(4):285–94.
DOI | Google Scholar
16
-
Van Der Heijde D, Keystone E. C., Curtis J. R., Landewé R. B., Schiff M. H., Khanna D, et al. Timing and magnitude of initial change in disease activity score 28 predicts the likelihood of achieving low disease activity at 1 year in rheumatoid arthritis patients treated with certolizumab pegol: a post-hoc analysis of the rapid 1 trial. The J of Rheum. 2012 May 15;39(7):1326–33.
DOI | Google Scholar
17
-
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. Rheumatoid arthritis classification criteria: an american college of rheumatology/European league against rheumatism collaborative initiative. Arth & Rheum. 2010;62(9):2569–81.
DOI | Google Scholar
18
-
Pollo GAV, Sumarauw SCP, Hessel SS, Tallei TE. Universal Primers for Amplification of TNF-α -308 Promoter Region. Pak J of Bio Sci. 2019 Nov 15;22(12):585–9.
DOI | Google Scholar
19
-
Yen, Jeng-Hsien, et al. Tumor necrosis factor receptor 2 microsatellite and exon 6 polymorphisms in rheumatoid arthritis in Taiwan. The J of Rheumatol.2003; 30(3), 438–442.
Google Scholar
20
-
Hall, T. A. BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Ac Sym Ser.1999; 41(41), 95–98.
Google Scholar
21
-
Kaijzel E, Bayley J-P, van Krugten M, Smith L, van de Linde P, Bakker A, et al. Allele-specific quantification of tumor necrosis factor α (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis patients and healthy individuals. Gene & Immu. 2001 May 1;2(3):135–44.
DOI | Google Scholar
22
-
Küçükaycan M, Van Krugten M, Pennings H-J, Huizinga TW, Buurman WA, Dentener MA, et al. Tumor Necrosis Factor-α +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease. Resp Res. 2002 Nov 29;3(1).
DOI | Google Scholar
23
-
Brennan F. Inhibitory effect of tnf$alpha; antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. The Lan. 1989 Jul;334(8657):244–7.
DOI | Google Scholar
24
-
You, Chong-ge, et al. Association analysis of single nucleotide polymorphisms of proinflammatory cytokine and their receptors genes with rheumatoid arthritis in northwest Chinese Han population. Cyto [Internet]. 2013 Jan 1 [cited 2021 Jun 2];61(1):133–8. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1043466612006977.
DOI | Google Scholar
25
-
Tokuhiro, Shinya, et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nature Genetics. 2003; 35(4), 341–348.
DOI | Google Scholar
26
-
Morita, Chika, et al. Association of tumor necrosis factor receptor type II polymorphism 196R with Systemic lupus erythematosus in the Japanese: molecular and functional analysis. Arth & Rheum: Off J of the Ame Coll of Rheumatol. 2001; 44(12), 2819–2827.
DOI | Google Scholar
27
-
Emonts M, Hazes MJ, Houwing-Duistermaat JJ, van der Gaast-de Jongh CE, de Vogel L, Han HK, et al. Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study. BMC Med Gen. 2011 Mar 7;12(1).
DOI | Google Scholar
28
-
Hussein YM, Mohamed RH, Pasha HF, El-Shahawy EE, Alzahrani SS. Association of tumor necrosis factor alpha and its receptor polymorphisms with rheumatoid arthritis in female patients. Cellular Immuno. 2011;271(1):192–6.
DOI | Google Scholar
29
-
Johnsen AK, Plenge RM, Butty V, Campbell C, Dieguez‐Gonzalez R, Gomez‐Reino JJ, et al. A broad analysis ofIL1polymorphism and rheumatoid arthritis. Arth & Rheum. 2008 Jul;58(7):1947–57.
DOI | Google Scholar
30
-
Kobayashi T, Murasawa A, Ito S, Yamamoto K, Komatsu Y, Abe A, et al. Cytokine gene polymorphisms associated with rheumatoid arthritis and periodontitis in Japanese adults. J of Periodonto. 2009 May;80(5):792–9.
DOI | Google Scholar
31
-
Jančić I, Šefik-Bukilica M, Živojinović S, Damjanov N, Spasovski V, Kotur N, et al. Influence of promoter polymorphisms of the tnf-α (-308g/a) and il-6 (-174g/c) genes on therapeutic response to etanercept in rheumatoid arthritis. J of Med Biochem. 2015 Oct 1;34(4):414–21.
DOI | Google Scholar
32
-
Mohammed S, Zalzala M, Gorial F. Association of tumor necrosis factor-alpha promoter region gene polymorphism at positions-308G/A, -857C/T, and -863C/A with etanercept response in Iraqi rheumatoid arthritis patients. Arch of Rheumato. 2022 Mar 3;37(4):613–25.
DOI | Google Scholar
33
-
Mugnier B, Balandraud N, Darque A, Roudier C, Roudier J, Reviron D. Polymorphism at position ?308 of the tumor necrosis factor? gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthr & Rheuma. 2003 Jul;48(7):1849–52.
DOI | Google Scholar
34
-
Guis S, Balandraud N, Bouvenot J, Auger I, Toussirot E, Wendling D, et al. Influence of −308 A/G polymorphism in the tumor necrosis factor α gene on etanercept treatment in rheumatoid arthritis. Arthr & Rheuma. 2007;57(8):1426–30.
DOI | Google Scholar
35
-
Cuchacovich M, Soto L, Edwardes M, Gutierrez M, Llanos C, Pacheco D, et al. Tumor necrosis factor (TNF)α −308 G/G promoter polymorphism and TNFα levels correlate with a better response to adalimumab in patients with rheumatoid arthritis. Scandin J of Rheumato. 2006 Jan;35(6):435–40.
DOI | Google Scholar
36
-
Swierkot J, Bogunia-Kubik K, Nowak B, Bialowas K, Korman L, Gebura K, et al. Analysis of associations between polymorphisms within genes coding for tumor necrosis factor (TNF)-alpha and TNF receptors and responsiveness to TNF-alpha blockers in patients with rheumatoid arthritis. Jo Bone Sp. 2015 Mar;82(2):94–9.
DOI | Google Scholar
37
-
Cimaz R, Cazalis M-A., Reynaud C, Gerloni V, Zulian F, Biggioggero M, et al. IL1 and TNF gene polymorphisms in patients with juvenile idiopathic arthritis treated with TNF inhibitors. Ann of the Rheum Dis. 2007 Feb 2;66(7):900–4.
DOI | Google Scholar
38
-
Scardapane A, Ferrante R, Nozzi M, Savino A, Antonucci I, Dadorante V, et al. TNF-α gene polymorphisms and juvenile idiopathic arthritis: Influence on disease outcome and therapeutic response. Sem in Arthr and Rheum. 2015 Aug;45(1):35–41.
DOI | Google Scholar
39
-
Tarnowski M, Paradowska-Gorycka A, Dąbrowska-Zamojcin E, Czerewaty M, Słuczanowska-Głąbowska S, Pawlik A. The effect of gene polymorphisms on patient responses to rheumatoid arthritis therapy. Exp Opi on Dru Meta & Toxico. 2015 Dec 8;12(1):41–55.
DOI | Google Scholar
40
-
Chatzikyriakidou A, Georgiou I, Voulgari PV, Venetsanopoulou AI, Drosos AA. Combined tumour necrosis factor and tumour necrosis factor receptor genotypes could predict rheumatoid arthritis patients’ response to anti-TNF therapy and explain controversies of studies based on a single polymorphism. Rheumato. 2007 Mar 27;46(6):1034–5.
DOI | Google Scholar
41
-
Vasilopoulos, Y., et al. Association of anti-CCP positivity and carriage of TNFRII susceptibility variant with anti-TNF-α response in rheumatoid arthritis. Clin and Exp Rheumatol.2011; 29(4), 701–704.
Google Scholar
42
-
Rooryck, C., et al. Influence of FCGR3A-V212F and TNFRSF1B-M196R genotypes in patients with rheumatoid arthritis treated with infliximab therapy. Clin and Exper Rheumatol.2008; 26(2), 340–342.
Google Scholar
43
-
Seitz M, Wirthmuller U, Moller B, Villiger PM. The -308 tumour necrosis factor-gene polymorphism predicts therapeutic response to TNF-blockers in rheumatoid arthritis and spondylarthritis patients. Rheumato. 2007 Jan 1;46(1):93–6.
DOI | Google Scholar
44
-
Canet LM, Filipescu I, Cáliz R, Lupiañez CB, Canhão H, Escudero A, et al. Genetic variants within the TNFRSF1B gene and susceptibility to rheumatoid arthritis and response to anti-TNF drugs. Pharma and Gen. 2015 Jul;25(7):323–33.
DOI | Google Scholar
45
-
Xing-rong W, Sheng-qian X, Wen L, Shan Q, Fa-ming P, Jian-hua X. Role of TNFRSF1A and TNFRSF1B polymorphisms in susceptibility, severity, and therapeutic efficacy of etanercept in human leukocyte antigen-B27-positive Chinese Han patients with ankylosing spondylitis. Med. 2018 Aug;97(31): e11677.
DOI | Google Scholar
46
-
Marotte H, Arnaud B, Diasparra J, Zrioual S, Miossec P. Association between the level of circulating bioactive tumor necrosis factor α and the tumor necrosis factor α gene polymorphism at−308 in patients with rheumatoid arthritis treated with a tumor necrosis factor α inhibitor. Arthr & Rheum. 2008;58(5):1258–63.
DOI | Google Scholar
47
-
Hadinedoushan H. Tumor necrosis factor alpha gene polymorphism and association with its serum level in iranian population with rheumatoid arthritis. Arch of Rheumato. 2016 Dec 5;31(4):306–13.
DOI | Google Scholar
48
-
Elahi MM, Asotra K, Matata BM, Mastana SS. Tumor necrosis factor alpha−308 gene locus promoter polymorphism: An analysis of association with health and disease. Bioch et Biophy Acta (BBA)-Mole Basis of Dis. 2009 Mar;1792(3):163–72.
DOI | Google Scholar
49
Most read articles by the same author(s)
-
Yassameen A. Hussain,
Khairallah A. S. Mohammed,
Naael H. Ali,
Potential Immunological Biomarker for Diagnosis and Prognosis of Tuberculosis , European Journal of Biomedical Research: Vol. 2 No. 1 (2023)