Fulya BAŞOĞLU KOSEAHMET, Candan EKER, Musa ÖZTÜRK, Şebnem ÖZDEMİR, Ayhan KÖKSAL, Sevim BAYBAS, Tuba GUNEL

The Role of rs4626 and rs7221352 Polymorphisms on the TOB1 Gene in Turkish Relapsing-Remitting Multiple Sclerosis Patients

Objective: Multiple sclerosis often causes neurological disability and reduced quality of life. Genetic biomarkers are important tools for the diagnosis and prognoses of diseases. This study has been conducted to explore the haplotype frequencies formed by rs4626 and rs7221352 single-nucleotide polymorphisms (SNPs) in the coding region variant (rs4626) and 5' upstream region intron variant (rs7221352) of the transducer of the ERBB2.1 (TOB1) gene in individuals with relapsingremitting multiple sclerosis. Materials and Methods: Thirty patients with an Expanded Disability Status Scale (EDSS) score<3, 30 patients with EDSS≥5, and 30 healthy controls participated in the study. The TOB1 rs4626 T/C and rs7221352 G/A single-base variations were applied using the quantitative real-time polymerase chain reaction method in accordance with the TaqMan SNP Genotyping Assays instructions. Results: The genotype frequencies of TOB1 rs4626 TT/TC/CC were respectively 3.3%, 53.3%, and 43.3% in the EDSS<3 cases and 10%, 53.3%, and 36.7% in the EDSS≥5 cases. The genotype frequencies of TOB1 rs7221352 GG/AG/AA were respectively 3.3%, 86.7%, and 10% in the EDSS<3 cases and 10%, 70%, and 20% in the EDSS≥5 cases. With respect to the estimated values in the study cohort, allelic variant frequency was higher in the patient group for both SNP variants (p<0.001). Conclusion: The presence of variant alleles in the rs4626 and rs7221352 polymorphisms in TOB1 may have a role in the disease immunopathogenesis. Further investigations involving larger groups are required to understand the effects of TOB1.

Keywords:

TOB1, multiple sclerosis, single-nucleotide polymorphisms, allelic variation, quantitative real-time PCR,

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1. Daroff RB, Fenichel GM, Jankovic, J. Bradley’s Neurology in Clinical Practice. 6th ed. Philadelphia: Elsevier Saunders Publishing; 2012. p.693-7. google scholar
2. Katsavos S, Anagnostouli M. Biomarkers in Multiple Sclerosis: An Up-to-Date Overview. Mult Scler Int 2013; 2013: 1-20. google scholar
3. Lin S, Zhu Q, Xu Y, Liu H, Zhang J, Xu J, et al. The role of the TOB1 gene in growth suppression of hepatocellular carcinoma. Oncol Lett 2012; 4: 981-7. google scholar
4. Salerno F, van Lier RAW, Wolkers MC. Better safe than sorry: TOB1 employs multiple parallel regulatory pathways to keep Th17 cells quiet. EurJ Immunol 2014;44:646-9. google scholar
5. NCBI (2022) Variation Viewer database [online] https://www.ncbi. nlm.nih.gov/variation/view [accessed on October, 2022]. google scholar
6. Ensembl (Release 107-2022). Ensembl database, Human (GRCh38. p13) build [online] https://www.ensembl.org/Homo_sapiens/Vari-ation, [accessed on October, 2022]. google scholar
7. Ensembl (Release 107-2022). Ensembl database, Human (GRCh38. p13) build [online] https://m.ensembl.org/info/genome/funcgen/ regulatory_build.html, [accessed on October, 2022]. google scholar
8. O’Malley S, Su H, Zhang T, Ng C, Ge H, Tang CK. TOB suppresses breast cancer tumorigenesis. Int J Cancer 2009; 125: 1805-13. google scholar
9. Park GT, Seo EY, Lee KM, Yang JM. Tob is a potential marker gene for the basal layer of the epidermis and is stably expressed in human primary keratinocytes. Br J Dermatol 2006; 154: 411-8. google scholar
10. Iwanaga K, Sueoka N, Sato A, Sakuragi T, Sakao Y, Tominaga M, et al. Alteration of expression or phosphorylation status of tob, a novel tumor suppressor gene product, is an early event in lung cancer. Cancer Lett 2003; 202: 71-9. google scholar
11. Jiao Y, Sun KK, Zhao L, Xu JY, Wang LL, Fan SJ. Suppression of human lung cancer cell proliferation and metastasis in vitro by the transducer of ErbB-2.1 (TOB1). Acta Pharmacol Sin 2012; 33: 25060. google scholar
12. Kundu J, Wahab SMR, Kundu JK, Choi YL, Erkin OC, Lee HS, et al. Tob1 induces apoptosis and inhibits proliferation, migration and invasion of gastric cancer cells by activating Smad4 and inhibiting ß-catenin signaling. Int J Oncol 2012;41:839-48. google scholar
13. Gebauer M, Saas J, Haag J, Dietz U, Takigawa M, Bartnik E, et al. Repression of anti-proliferative factor Tob1 in osteoarthritic cartilage. Arthritis Res Ther 2005; 7: R274-84. google scholar
14. Tzachanis D, Freeman GJ, Hirano N, van Puijenbroek AAFL, Delfs MW, Berezovskaya A, et al. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol 2001; 2: 1174-82. google scholar
15. Ikematsu N, Yoshida Y, Kawamura-Tsuzuku J, Ohsugi M, Onda M, Hirai M, et al. Tob2, a novel anti-proliferative Tob/BTG1 family member, associates with a component of the CCR4 transcriptional regulatory complex capable of binding cyclin-dependent kinases. Oncogene 1999; 18: 7432-41. google scholar
16. Schulze-Topphoff U, Casazza S, Varrin-Doyer M, Pekarek K, Sobel RA, Hauser SL, et al. Tob1 plays a critical role in the activation of en-cephalitogenic T cells in CNS autoimmunity. J Exp Med 2013; 210: 1301-9. google scholar
17. Tzachanis D, Boussiotis VA. Tob, a member of the APRO family, regulates immunological quiescence and tumor suppression. Cell Cycle 2009; 8: 1019-25. google scholar
18. Corvol JC, Pelletier D, Henry RG, Caillier SJ, Wang J, Pappas D, et al. Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event. Proc Natl Acad Sci USA 2008; 105: 11839-44. google scholar
19. Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955; 19: 251-3. google scholar
20. Gene Calc-Szymon Miks, Jan Binkowski portal website, (2022), https://gene-calc.pl/hardy-weinberg-page, [accessed on November, 2022]. google scholar
21. GTEx Portal website (2022), https://www.gtexportal.org/, [accessed on November, 2022]. google scholar
22. Nielsen NM, Westergaard T, Rostgaard K, Frisch M, Hjalgrim H, Wohlfahr J, et al. Familial risk of multiple sclerosis: a nationwide cohort study. Am J Epidemiol 2005; 162: 774-8. google scholar
23. Baranzini SE, Oksenberg JR. The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years. Trends Genet 2017; 33: 960-70. google scholar
24. Patsopoulos NA, Baranzini SE, Santaniello A, Shoostari P, Cotsa-pas C, Wong G, et al. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 2019; 365: 1-25. google scholar
25. Mansilla MJ, Presas-Rodríguez S, Teniente-Serra A, González-Lar-reategui I, Quirant-Sánchez B, Fondelli F, et al. Paving the way towards an effective treatment for multiple sclerosis: advances in cell therapy.Cell Mol Immunol 2021; 18:1353-74. google scholar
26. Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, Cotsapas C, et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013; 45: 1353-60. google scholar
27. Baranzini SE. The role of antiproliferative gene Tob1 in the immune system. Clin Exp Neuroimmunol 2014; 5: 132-6. google scholar
28. Ensembl (Release 107-2022), rs4626 SNP ensemble genome browser information page, http://www.ensembl.org/Homo_sapi-ens/Variation/Explore?r=17:50862561- 50863561;v=rs4626;vdb=-variation;vf=87138538 [accessed on October, 2022]. google scholar
29. Ensembl (Release 107-2022), rs7221352 SNP ensemble genome browser information page, http://www.ensembl.org/Homo_sapi-ens/Variation/Explore?r=17:50869364- 50870364;v=rs7221352;vd-b=variation;vf=88123893 [accessed on October, 2022]. google scholar
30. Gresle MM, Jordan MA, Stankovich J, Spelman T, Johnson LJ, Laver-ick L, et al. Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells. Life Sci Alliance 2020; 3: 1-11. google scholar