S1PR1 genetic variants may modulate disability outcomes and therapy response in relapsing-remitting multiple sclerosis

Authors

  • Miloš B. Danilović Military Medical Academy, Clinic for Neurology, Crnotravska 17, Belgrade, Serbia https://orcid.org/0000-0003-3299-5404
  • Ivan R. Životić VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade, Serbia https://orcid.org/0000-0002-5073-5537
  • Ivana Z. Kolić VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade, Serbia https://orcid.org/0000-0002-7656-5708
  • Milan B. Stefanović VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade, Serbia https://orcid.org/0000-0003-4272-2370
  • Evica R. Dinčić 1. Military Medical Academy, Clinic for Neurology, Crnotravska 17, Belgrade, Serbia; 2. Faculty of Medicine of the Military Medical Academy, University of Defense, Crnotravska 17, Belgrade, Serbia https://orcid.org/0009-0007-2945-6561
  • Aleksandra D. Stanković Military Medical Academy, Clinic for Neurology, Crnotravska 17, Belgrade, Serbia; Faculty of Medicine of the Military Medical Academy, University of Defense, Crnotravska 17, Belgrade, Serbia https://orcid.org/0000-0002-1050-5913
  • Maja D. Živković VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade, Serbia https://orcid.org/0000-0002-0447-6626

DOI:

https://doi.org/10.2298/ABS260313011D

Keywords:

S1PR1, modulating therapy, multiple sclerosis, therapy response

Abstract

Paper description:

  • S1PR1 modulators are an effective therapy for relapsing-remitting multiple sclerosis, yet therapy response shows heterogeneity. S1PR1 genetic variation may influence receptor function and therapeutic binding.
  • Targeted Sanger sequencing of the 5′ genomic region of the S1PR1 gene was performed in 31 RRMS patients from Serbia to investigate genetic variability in the coding regions relevant for response to therapy.
  • Identification of polymorphic genetic variants revealed three variants: rs41287280, rs3737577 and rs3737578 of which rs41287280 was associated with disability outcomes and showed a trend toward association with therapy response.
  • In multivariable regression models, rs41287280 and rs3737577 were associated with disease severity, measured by disability outcomes.

Abstract: Sphingosine-1-phosphate receptor 1 (S1PR1) modulators are an effective therapy for patients with relapsing-remitting multiple sclerosis (RRMS), although considerable inter-individual variability in treatment response remains. This study aimed to investigate genetic variability within the coding regions of S1PR1 and to assess its potential association with treatment response and clinical disability measures, including the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS), in patients with RRMS. Thirty-one RRMS patients from Serbia underwent sequencing of the 5′ regulatory region and coding exons of S1PR1 using an Applied Biosystems 3130 Genetic Analyzer. Three polymorphic variants were identified. None of the analyzed variants demonstrated a significant association with treatment response. Despite the small sample size, rs41287280 showed a significant association with disability measures; in a dominant inheritance model, carriers of the G allele had lower EDSS and MSSS values (P=0.01 and P=0.006, respectively) compared with the CC genotype. In multivariable analyses, the rs41287280 G allele was associated with lower disability, whereas the rs3737577 T allele was associated with higher disability compared to the wild-type GG genotype after adjustment. These results provide preliminary evidence suggesting that S1PR1 genetic variation may be related to disease pathogenesis in RRMS, warranting further confirmation in larger, independent cohorts and, potentially, functional investigation.

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References

Lassmann H. Multiple Sclerosis Pathology. Cold Spring Harb Perspect Med. 2018;8(3):a028936. https://doi.org/10.1101/cshperspect.a028936

Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, Robertson N, La Rocca N, Uitdehaag B, van der Mei I, Wallin M, Helme A, Angood Napier C, Rijke N, Baneke P. Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult Scler. 2020;26(14):1816-21. https://doi.org/10.1177/1352458520970841

Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. https://doi.org/10.1056/NEJMoa0909494

Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, Li B, Cappiello L, von Rosenstiel P, Lublin FD. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(6):545-56. https://doi.org/10.1016/S1474-4422(14)70049-3

Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427(6972):355-60. https://doi.org/10.1038/nature02284

Grigorova IL, Schwab SR, Phan TG, Pham TH, Okada T, Cyster JG. Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells. Nat Immunol. 2009;10(1):58-65. https://doi.org/10.1038/ni.1682

Cavone L, Felici R, Lapucci A, Buonvicino D, Pratesi S, Muzzi M, Hakiki B, Maggi L, Peruzzi B, Caporale R, Annunziato F, Amato MP, Chiarugi A. Dysregulation of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound. Brain Behav Immun. 2015;50:78-86. https://doi.org/10.1016/j.bbi.2015.06.019

Don-Doncow N, Vanherle L, Zhang Y, Meissner A. T-Cell Accumulation in the Hypertensive Brain: A Role for Sphingosine-1-Phosphate-Mediated Chemotaxis. Int J Mol Sci. 2019;20(3):537. https://doi.org/10.3390/ijms20030537

Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002;277(24):21453-7. https://doi.org/10.1074/jbc.C200176200

Gräler MH, Goetzl EJ. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J. 2004;18(3):551-3. https://doi.org/10.1096/fj.03-0910fje

Wu C, Leong SY, Moore CS, Cui QL, Gris P, Bernier LP, Johnson TA, Séguéla P, Kennedy TE, Bar-Or A, Antel JP. Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation. J Neuroinflammation. 2013;10:41. https://doi.org/10.1186/1742-2094-10-41

Kalincik T, Manouchehrinia A, Sobisek L, Jokubaitis V, Spelman T, Horakova D, Havrdova E, Trojano M, Izquierdo G, Lugaresi A, Girard M, Prat A, Duquette P, Grammond P, Sola P, Hupperts R, Grand'Maison F, Pucci E, Boz C, Alroughani R, Van Pesch V, Lechner-Scott J, Terzi M, Bergamaschi R, Iuliano G, Granella F, Spitaleri D, Shaygannejad V, Oreja-Guevara C, Slee M, Ampapa R, Verheul F, McCombe P, Olascoaga J, Amato MP, Vucic S, Hodgkinson S, Ramo-Tello C, Flechter S, Cristiano E, Rozsa C, Moore F, Luis Sanchez-Menoyo J, Laura Saladino M, Barnett M, Hillert J, Butzkueven H; MSBase Study Group. Towards personalized therapy for multiple sclerosis: prediction of individual treatment response. Brain. 2017;140(9):2426-43. https://doi.org/10.1093/brain/awx185

Kalincik T, Diouf I, Sharmin S, Malpas C, Spelman T, Horakova D, Havrdova EK, Trojano M, Izquierdo G, Lugaresi A, Prat A, Girard M, Duquette P, Grammond P, Jokubaitis V, van der Walt A, Grand'Maison F, Sola P, Ferraro D, Shaygannejad V, Alroughani R, Hupperts R, Terzi M, Boz C, Lechner-Scott J, Pucci E, Van Pesch V, Granella F, Bergamaschi R, Spitaleri D, Slee M, Vucic S, Ampapa R, McCombe P, Ramo-Tello C, Prevost J, Olascoaga J, Cristiano E, Barnett M, Saladino ML, Sanchez-Menoyo JL, Hodgkinson S, Rozsa C, Hughes S, Moore F, Shaw C, Butler E, Skibina O, Gray O, Kermode A, Csepany T, Singhal B, Shuey N, Piroska I, Taylor B, Simo M, Sirbu CA, Sas A, Butzkueven H; MSBase Study Group. Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years. Neurology. 2021;96(5):e783-97. https://doi.org/10.1212/WNL.0000000000011242

Callegari I, Derfuss T, Galli E. Update on treatment in multiple sclerosis. Presse Med. 2021;50(2):104068. https://doi.org/10.1016/j.lpm.2021.104068

Lee CY, Chan KH. Personalized Use of Disease-Modifying Therapies in Multiple Sclerosis. Pharmaceutics. 2024;16(1):120. https://doi.org/10.3390/pharmaceutics16010120

Chen S, Wu L, Lang B, Zhao G, Zhang W. Sphingosine 1-phosphate receptor 1 modulators exert neuroprotective effects in central nervous system disorders. Front Pharmacol. 2025;16:1516991. https://doi.org/10.3389/fphar.2025.1516991

Obinata H, Gutkind S, Stitham J, Okuno T, Yokomizo T, Hwa J, Hla T. Individual variation of human S1P1 coding sequence leads to heterogeneity in receptor function and drug interactions [S]. J Lipid Res. 2014;55(12):2665-75. https://doi.org/10.1194/jlr.P054163

Kores K, Lešnik S, Bren U. Computational Analysis of S1PR1 SNPs Reveals Drug Binding Modes Relevant to Multiple Sclerosis Treatment. Pharmaceutics. 2024;16(11):1413. https://doi.org/10.3390/pharmaceutics16111413

Hočevar K, Ristić S, Peterlin B. Pharmacogenomics of Multiple Sclerosis: A Systematic Review. Front Neurol. 2019;10:134. https://doi.org/10.3389/fneur.2019.00134

Ferrè L, Clarelli F, Pignolet B, Mascia E, Frasca M, Santoro S, Sorosina M, Bucciarelli F, Moiola L, Martinelli V, Comi G, Liblau R, Filippi M, Valentini G, Esposito F. Combining Clinical and Genetic Data to Predict Response to Fingolimod Treatment in Relapsing Remitting Multiple Sclerosis Patients: A Precision Medicine Approach. J Pers Med. 2023;13(1):122. https://doi.org/10.3390/jpm13010122

Yu L, He L, Gan B, Ti R, Xiao Q, Hu H, Zhu L, Wang S, Ren R. Structural insights into sphingosine-1-phosphate receptor activation. Proc Natl Acad Sci U S A. 2022;119(16):e2117716119. https://doi.org/10.1073/pnas.2117716119

Moore JE, Pratt HE, Fan K, Phalke N, Fisher J, Elhajjajy SI, Andrews G, Gao M, Shedd N, Fu Y, Lacadie MC, Meza J, Khandpekar M, Ganna M, Choudhury E, Swofford R, Phan H, Ramirez CC, Campbell M, Likhite M, Farrell NP, Weimer AK, Pampari A, Ramalingam V, Reese F, Borsari B, Yu X, Wattenberg E, Ruiz-Romero M, Razavi-Mohseni M, Xu J, Galeev T, Colubri A, Beer MA, Guigó R, Gerstein MB, Engreitz JM, Ljungman M, Reddy TE, Snyder MP, Epstein CB, Gaskell E, Bernstein BE, Dickel DE, Visel A, Pennacchio LA, Mortazavi A, Kundaje A, Weng Z. An expanded registry of candidate cis-regulatory elements. Nature. 2026. https://doi.org/10.1038/s41586-025-09909-9

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302. https://doi.org/10.1002/ana.22366

Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintoré M, Traboulsee AL, Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-73. https://doi.org/10.1016/S1474-4422(17)30470-2

Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stüve O, Waubant E, Polman CH. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-86. https://doi.org/10.1212/WNL.0000000000000560

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444-52. https://doi.org/10.1212/wnl.33.11.1444

Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, Achiti I, Confavreux C, Coustans M, le Page E, Edan G, McDonnell GV, Hawkins S, Trojano M, Liguori M, Cocco E, Marrosu MG, Tesser F, Leone MA, Weber A, Zipp F, Miterski B, Epplen JT, Oturai A, Sørensen PS, Celius EG, Lara NT, Montalban X, Villoslada P, Silva AM, Marta M, Leite I, Dubois B, Rubio J, Butzkueven H, Kilpatrick T, Mycko MP, Selmaj KW, Rio ME, Sá M, Salemi G, Savettieri G, Hillert J, Compston DA. Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology. 2005;64(7):1144-51. https://doi.org/10.1212/01.WNL.0000156155.19270.F8

Coyle PK. Pharmacogenetic Biomarkers to Predict Treatment Response in Multiple Sclerosis: Current and Future Perspectives. Mult Scler Int. 2017;2017:6198530. https://doi.org/10.1155/2017/6198530

Swallow E, Pham T, Patterson-Lomba O, Yin L, Gomez-Lievano A, Liu J, Tencer T, Gupte-Singh K. Comparative efficacy and safety of ozanimod and ponesimod for relapsing multiple sclerosis: A matching-adjusted indirect comparison. Mult Scler Relat Disord. 2023;71:104551. https://doi.org/10.1016/j.msard.2023.104551

UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025. Nucleic Acids Res. 2025;53(D1):D609-17. https://doi.org/10.1093/nar/gkae1010

Dyer SC, Austine-Orimoloye O, Azov AG, Barba M, Barnes I, Barrera-Enriquez VP, Becker A, Bennett R, Beracochea M, Berry A, Bhai J, Bhurji SK, Boddu S, Branco Lins PR, Brooks L, Ramaraju SB, Campbell LI, Martinez MC, Charkhchi M, Cortes LA, Davidson C, Denni S, Dodiya K, Donaldson S, El Houdaigui B, El Naboulsi T, Falola O, Fatima R, Genez T, Martinez JG, Gurbich T, Hardy M, Hollis Z, Hunt T, Kay M, Kaykala V, Lemos D, Lodha D, Mathlouthi N, Merino GA, Merritt R, Mirabueno LP, Mushtaq A, Hossain SN, Pérez-Silva JG, Perry M, Piližota I, Poppleton D, Prosovetskaia I, Raj S, Salam AIA, Saraf S, Saraiva-Agostinho N, Sinha S, Sipos B, Sitnik V, Steed E, Suner MM, Surapaneni L, Sutinen K, Tricomi FF, Tsang I, Urbina-Gómez D, Veidenberg A, Walsh TA, Willhoft NL, Allen J, Alvarez-Jarreta J, Chakiachvili M, Cheema J, da Rocha JB, De Silva NH, Giorgetti S, Haggerty L, Ilsley GR, Keatley J, Loveland JE, Moore B, Mudge JM, Naamati G, Tate J, Trevanion SJ, Winterbottom A, Flint B, Frankish A, Hunt SE, Finn RD, Freeberg MA, Harrison PW, Martin FJ, Yates AD. Ensembl 2025. Nucleic Acids Res. 2025;53(D1):D948-57. https://doi.org/10.1093/nar/gkae1071

Astle WJ, Elding H, Jiang T, Allen D, Ruklisa D, Mann AL, Mead D, Bouman H, Riveros-Mckay F, Kostadima MA, Lambourne JJ, Sivapalaratnam S, Downes K, Kundu K, Bomba L, Berentsen K, Bradley JR, Daugherty LC, Delaneau O, Freson K, Garner SF, Grassi L, Guerrero J, Haimel M, Janssen-Megens EM, Kaan A, Kamat M, Kim B, Mandoli A, Marchini J, Martens JHA, Meacham S, Megy K, O'Connell J, Petersen R, Sharifi N, Sheard SM, Staley JR, Tuna S, van der Ent M, Walter K, Wang SY, Wheeler E, Wilder SP, Iotchkova V, Moore C, Sambrook J, Stunnenberg HG, Di Angelantonio E, Kaptoge S, Kuijpers TW, Carrillo-de-Santa-Pau E, Juan D, Rico D, Valencia A, Chen L, Ge B, Vasquez L, Kwan T, Garrido-Martín D, Watt S, Yang Y, Guigo R, Beck S, Paul DS, Pastinen T, Bujold D, Bourque G, Frontini M, Danesh J, Roberts DJ, Ouwehand WH, Butterworth AS, Soranzo N. The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease. Cell. 2016;167(5):1415-29.e19. https://doi.org/10.1016/j.cell.2016.10.042

Moheghi N, Sasannezhad P, John Walley A. No Association between Single-Nucleotide Polymorphisms of The S1PR1 Gene or Interleukin-17 Levels with Fingolimod Response in A Small Group of Iranian Relapsing-Remitting Multiple Sclerosis Patients: A Case-Control Study. Cell J. 2024;26(3):185-93. https://doi.org/10.22074/cellj.2024.2012548.1415

Derfuss T, Sastre-Garriga J, Montalban X, Rodegher M, Wuerfel J, Gaetano L, Tomic D, Azmon A, Wolf C, Kappos L. The ACROSS study: Long-term efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis. Mult Scler J Exp Transl Clin. 2020;6(1):2055217320907951. https://doi.org/10.1177/2055217320907951

Van Doorn R, Van Horssen J, Verzijl D, Witte M, Ronken E, Van Het Hof B, Lakeman K, Dijkstra CD, Van Der Valk P, Reijerkerk A, Alewijnse AE, Peters SL, De Vries HE. Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia. 2010;58(12):1465-76. https://doi.org/10.1002/glia.21021

Cartier A, Hla T. Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science. 2019;366(6463):eaar5551. https://doi.org/10.1126/science.aar5551

Maeda Y, Seki N, Kataoka H, Takemoto K, Utsumi H, Fukunari A, Sugahara K, Chiba K. IL-17-Producing Vγ4+ γδ T Cells Require Sphingosine 1-Phosphate Receptor 1 for Their Egress from the Lymph Nodes under Homeostatic and Inflammatory Conditions. J Immunol. 2015;195(4):1408-16. https://doi.org/10.4049/jimmunol.1500599

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2026-07-09

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Danilović MB, Životić IR, Kolić IZ, Stefanović MB, Dinčić ER, Stanković AD, Živković MD. S1PR1 genetic variants may modulate disability outcomes and therapy response in relapsing-remitting multiple sclerosis. Arch Biol Sci [Internet]. 2026Jul.9 [cited 2026Jul.11];78(2):179-8. Available from: https://www.serbiosoc.org.rs/arch/index.php/abs/article/view/12285

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Vol. 78 No. 2 (2026)

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Copyright (c) 2026 Ivan Životić, Miloš Danilović, Ivana Kolić, Milan Stefanović, Evica Dinčić, Aleksandra Stanković, Maja Živković

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