Interleukin 6 SNP rs1818879 Regulates Radiological and Inflammatory Activity in Multiple Sclerosis
Abstract
:1. Introduction
2. Materials and Methods
2.1. MS Patients
2.2. IL-6 SNPs Analysis
2.3. CSF Collection and Analysis
2.4. MRI
2.5. Statistical Analysis
3. Results
3.1. Clinical Characteristics in MS Patients
3.2. Analysis of IL-6 SNP
3.3. Association between CSF Inflammation and IL-6 SNPs
3.4. rs1818879 Influences Radiological Activity in RRMS Patients
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Thompson, A.J.; Baranzini, S.E.; Geurts, J.; Hemmer, B.; Ciccarelli, O. Multiple sclerosis. Lancet 2018, 391, 1622–1636. [Google Scholar] [CrossRef]
- Göbel, K.; Ruck, T.; Meuth, S.G. Cytokine signaling in multiple sclerosis: Lost in translation. Mult. Scler. J. 2018, 24, 432–439. [Google Scholar] [CrossRef] [PubMed]
- Codarri, L.; Fontana, A.; Becher, B. Cytokine networks in multiple sclerosis: Lost in translation. Curr. Opin. Neurol. 2010, 23, 205–211. [Google Scholar] [CrossRef]
- Yadav, S.K.; Mindur, J.E.; Ito, K.; Dhib-Jalbut, S. Advances in the immunopathogenesis of multiple sclerosis. Curr. Opin. Neurol. 2015, 28, 206–219. [Google Scholar] [CrossRef] [PubMed]
- Becher, B.; Spath, S.; Goverman, J. Cytokine networks in neuroinflammation. Nat. Rev. Immunol. 2017, 17, 49–59. [Google Scholar] [CrossRef] [PubMed]
- Stampanoni Bassi, M.; Iezzi, E.; Mori, F.; Simonelli, I.; Gilio, L.; Buttari, F.; Sica, F.; De Paolis, N.; Mandolesi, G.; Musella, A.; et al. Interleukin-6 Disrupts Synaptic Plasticity and Impairs Tissue Damage Compensation in Multiple Sclerosis. Neurorehabil. Neural Repair 2019, 33, 825–835. [Google Scholar] [CrossRef]
- Stampanoni Bassi, M.; Iezzi, E.; Drulovic, J.; Pekmezovic, T.; Gilio, L.; Furlan, R.; Finardi, A.; Marfia, G.A.; Sica, F.; Centonze, D.; et al. IL-6 in the Cerebrospinal Fluid Signals Disease Activity in Multiple Sclerosis. Front. Cell. Neurosci. 2020, 14, 120. [Google Scholar] [CrossRef]
- Kleiter, I.; Ayzenberg, I.; Araki, M.; Yamamura, T.; Gold, R. Tocilizumab, MS, and NMOSD. Mult. Scler. J. 2016, 22, 1891–1892. [Google Scholar] [CrossRef]
- Rothaug, M.; Becker-Pauly, C.; Rose-John, S. The role of interleukin-6 signaling in nervous tissue. Biochim. Biophys. Acta-Mol. Cell Res. 2016, 1863, 1218–1227. [Google Scholar] [CrossRef]
- Mirowska-Guzel, D.; Gromadzka, G.; Mach, A.; Czlonkowski, A.; Czlonkowska, A. Association of IL1A, IL1B, ILRN, IL6, IL10 and TNF-α polymorphisms with risk and clinical course of multiple sclerosis in a Polish population. J. Neuroimmunol. 2011, 236, 87–92. [Google Scholar] [CrossRef]
- Benešová, Y.; Vašků, A.; Bienertová-Vašků, J. Association of interleukin 6, interleukin 7 receptor alpha, and interleukin 12B gene polymorphisms with multiple sclerosis. Acta Neurol. Belg. 2018, 118, 493–501. [Google Scholar] [CrossRef] [PubMed]
- Helmy, A.; Antoniades, C.A.; Guilfoyle, M.R.; Carpenter, K.L.H.; Hutchinson, P.J. Principal Component Analysis of the Cytokine and Chemokine Response to Human Traumatic Brain Injury. PLoS ONE 2012, 7, e39677. [Google Scholar] [CrossRef]
- Musella, A.; Fresegna, D.; Rizzo, F.R.; Gentile, A.; De Vito, F.; Caioli, S.; Guadalupi, L.; Bruno, A.; Dolcetti, E.; Buttari, F.; et al. ‘Prototypical’ proinflammatory cytokine (IL-1) in multiple sclerosis: Role in pathogenesis and therapeutic targeting. Expert Opin. Ther. Targets 2020, 24, 37–46. [Google Scholar] [CrossRef] [PubMed]
- Mandolesi, G.; Gentile, A.; Musella, A.; Fresegna, D.; De Vito, F.; Bullitta, S.; Sepman, H.; Marfia, G.A.; Centonze, D. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat. Rev. Neurol. 2015, 11, 711–724. [Google Scholar] [CrossRef] [PubMed]
- Rossi, S.; Studer, V.; Motta, C.; Germani, G.; Macchiarulo, G.; Buttari, F.; Mancino, R.; Castelli, M.; De Chiara, V.; Weiss, S.; et al. Cerebrospinal fluid detection of interleukin-1β in phase of remission predicts disease progression in multiple sclerosis. J. Neuroinflamm. 2014, 11, 32. [Google Scholar] [CrossRef] [Green Version]
- Ruocco, G.; Rossi, S.; Motta, C.; Macchiarulo, G.; Barbieri, F.; De Bardi, M.; Borsellino, G.; Finardi, A.; Grasso, M.G.; Ruggieri, S.; et al. T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis. Clin. Sci. 2015, 129, 291–303. [Google Scholar] [CrossRef] [Green Version]
- Donninelli, G.; Studer, V.; Brambilla, L.; Zecca, C.; Peluso, D.; Laroni, A.; Michelis, D.; Mantegazza, R.; Confalonieri, P.; Volpe, E. Immune Soluble Factors in the Cerebrospinal Fluid of Progressive Multiple Sclerosis Patients Segregate into Two Groups. Front. Immunol. 2021, 12, 633167. [Google Scholar] [CrossRef]
- Sedeeq, M.S.; El-Nahrery, E.M.A.; Shalaby, N.; Hussein, M.; Shehata, H.; El Aal, R.A.; Abdel Ghaffar, N.F.; Mohamed, M.M. Micro-RNA-96 and interleukin-10 are independent biomarkers for multiple sclerosis activity. J. Neurol. Sci. 2019, 403, 92–96. [Google Scholar] [CrossRef]
- Rossi, S.; Mancino, R.; Bergami, A.; Mori, F.; Castelli, M.; De Chiara, V.; Studer, V.; Mataluni, G.; Sancesario, G.; Parisi, V.; et al. Potential role of IL-13 in neuroprotection and cortical excitability regulation in multiple sclerosis. Mult. Scler. J. 2011, 17, 1301–1312. [Google Scholar] [CrossRef]
- Elyaman, W.; Khoury, S.J. Th9 cells in the pathogenesis of EAE and multiple sclerosis. Semin. Immunopathol. 2017, 39, 79–87. [Google Scholar] [CrossRef]
- Yan, J.; Liu, J.; Lin, C.Y.; Csurhes, P.A.; Pender, M.P.; McCombe, P.A.; Greer, J.M. Interleukin-6 Gene Promoter-572 C Allele May Play a Role in Rate of Disease Progression in Multiple Sclerosis. Int. J. Mol. Sci. 2012, 13, 13667–13679. [Google Scholar] [CrossRef] [Green Version]
- Stonys, V.; Lindžiūtė, M.; Vilkevičiūtė, A.; Gedvilaitė, G.; Kriaučiūnienė, L.; Banevičius, M.; Žemaitienė, R.; Liutkevičienė, R. Associations between IL1RAP rs4624606, IL1RL1 rs1041973, IL-6 rs1800795, and HTRA1 rs11200638 gene polymorphisms and development of optic neuritis with or without multiple sclerosis. Ophthalmic Genet. 2020, 41, 325–330. [Google Scholar] [CrossRef] [PubMed]
- Gedvilaite, G.; Vilkeviciute, A.; Kriauciuniene, L.; Asmoniene, V.; Liutkeviciene, R. Does CETP rs5882, rs708272, SIRT1 rs12778366, FGFR2 rs2981582, STAT3 rs744166, VEGFA rs833068, IL6 rs1800795 polymorphisms play a role in optic neuritis development? Ophthalmic Genet. 2019, 40, 219–226. [Google Scholar] [CrossRef] [PubMed]
- Bertoli, D.; Serana, F.; Sottini, A.; Cordioli, C.; Maimone, D.; Amato, M.P.; Centonze, D.; Florio, C.; Puma, E.; Capra, R.; et al. Less Frequent and Less Severe Flu-Like Syndrome in Interferon β-1a Treated Multiple Sclerosis Patients with at Least One Allele Bearing the G > C Polymorphism at Position -174 of the IL-6 Promoter Gene. PLoS ONE 2015, 10, e0135441. [Google Scholar] [CrossRef]
- Hu, S.; Chen, Y.; Sun, X.-D.; Li, F.-J.; Shu, Q.-F.; Liu, X.-L.; Jiang, S.-F. Association between IL-6 -174G/C Polymorphism and Risk of Multiple Sclerosis: A Meta-Analysis. Genet. Test. Mol. Biomark. 2014, 18, 127–130. [Google Scholar] [CrossRef] [PubMed]
- Amirzargar, A.; Khosravi, F.; Dianat, S.; Hushmand, F.; Maryousef, P.; Foroushani, A.; Lotfi, J.; Nikbin, B. Profile of cytokine gene polymorphisms in Iranian multiple sclerosis patients. Mult. Scler. J. 2007, 13, 253–255. [Google Scholar] [CrossRef]
- Paradowska-Gorycka, A.; Roszak, M.; Stypinska, B.; Lutkowska, A.; Walczyk, M.; Olesinska, M.; Wajda, A.; Piotrowski, P.; Puszczewicz, M.; Majewski, D.; et al. IL-6 and TGF-β gene polymorphisms, their serum levels, as well as HLA profile, in patients with systemic lupus erythematosus. Clin. Exp. Rheumatol. 2019, 37, 963–975. [Google Scholar]
- Dar, S.A.; Haque, S.; Mandal, R.K.; Singh, T.; Wahid, M.; Jawed, A.; Panda, A.K.; Akhter, N.; Lohani, M.; Areeshi, M.Y.; et al. Interleukin-6-174G > C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: A case-control study and meta-analysis. Autoimmunity 2017, 50, 158–169. [Google Scholar] [CrossRef]
- Ambrocio-Ortiz, E.; Pérez-Rubio, G.; Abarca-Rojano, E.; Montaño, M.; Ramos, C.; Hernández-Zenteno, R.D.J.; Del Angel-Pablo, A.D.; Reséndiz-Hernández, J.M.; Ramírez-Venegas, A.; Falfán-Valencia, R. Influence of proinflammatory cytokine gene polymorphisms on the risk of COPD and the levels of plasma protein. Cytokine 2018, 111, 364–370. [Google Scholar] [CrossRef]
- Cohen-Woods, S.; Fisher, H.L.; Ahmetspahic, D.; Douroudis, K.; Stacey, D.; Hosang, G.M.; Korszun, A.; Owen, M.; Craddock, N.; Arolt, V.; et al. Interaction between childhood maltreatment on immunogenetic risk in depression: Discovery and replication in clinical case-control samples. Brain. Behav. Immun. 2018, 67, 203–210. [Google Scholar] [CrossRef] [Green Version]
- Kaboré, J.W.; Ilboudo, H.; Noyes, H.; Camara, O.; Kaboré, J.; Camara, M.; Koffi, M.; Lejon, V.; Jamonneau, V.; MacLeod, A.; et al. Candidate gene polymorphisms study between human African trypanosomiasis clinical phenotypes in Guinea. PLoS Negl. Trop. Dis. 2017, 11, e0005833. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kim, S.; Yu, N.-K.; Kaang, B.-K. CTCF as a multifunctional protein in genome regulation and gene expression. Exp. Mol. Med. 2015, 47, e166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stampanoni Bassi, M.; Gilio, L.; Maffei, P.; Dolcetti, E.; Bruno, A.; Buttari, F.; Centonze, D.; Iezzi, E. Exploiting the Multifaceted Effects of Cannabinoids on Mood to Boost Their Therapeutic Use Against Anxiety and Depression. Front. Mol. Neurosci. 2018, 11, 424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
MS Patients n = 171 | ||
---|---|---|
Sex, F | N (%) | 113 (66.10) |
Age, years | Mean, (SD) | 35.78 (12.27) |
Disease duration, months | Median, (IQR) | 5.10 (1.05–24.89) |
EDSS at diagnosis | Median, (IQR) | 2 (1–2.5) |
OCB presence, yes | N (%) | 132/166 (79.50) |
Radiological activity at diagnosis | N (%) | 74/166 (44.60) |
Clinical activity at diagnosis | N (%) | 68 (39.76) |
SNP | SNP Distribution | Allele Frequency (%) | Chi-Square | Group Analysis (n) |
---|---|---|---|---|
rs1818879 | GG (n = 88; 51.46%) AG (n = 79; 46.19%) AA (n = 4; 2.33%) | G = 75.44 A = 24.55 | p = 0.917 | GG (88) AG/AA (83) |
rs1554606 | GG (n = 78; 70.38%) TG (n = 46; 32.11%) TT (n = 11; 6.58%) | G = 74.81 T = 25.18 | p = 0.842 | GG (78) TG/TT (57) |
rs1800797 | GG (n = 86; 50.58%) AG (n = 74; 41.17%) AA (n = 10; 5.88%) | G = 72.35 A = 27.64 | p = 0.886 | GG (86) AG/AA (84) |
rs1474347 | AA (n = 84; 49.70%) CA (n = 75; 44.37%) CC (n = 10; 5.91%) | A = 71.81 C = 28.19 | p = 0.870 | AA (84) CA/CC (85) |
GG | AG/AA | p Value | β-Coefficient | SE | |
---|---|---|---|---|---|
IL-1β | 0.01 (0.01–0.05) | 0.025 (0.00–0.07) | p = 0. 0385 * | 7.00 | 3.38 |
IL-4 | 0.08 (0.01–0.15) | 0.08 (0.00–0.22) | p = 0.104 | 1.25 | 0.770 |
IL-5 | 0.34 (0.00–2.16) | 1.15 (0.00–3.34) | p = 0.0543 | 0.142 | 0.0740 |
IL-7 | 0.41 (0.00–0.92) | 0.20 (0.00–1.41) | p = 0.0991 | 0.180 | 0.109 |
IL-9 | 1.86 (1.11–2.77) | 2.36 (1.45–5.44) | p = 0.0231 * | 0.105 | 0.0462 |
IL-10 | 1.78 (0.97–2.60) | 2.11 (1.27–2.70) | p = 0.0345 * | 0.278 | 0.132 |
IL-13 | 1.63 (1.04–3.32) | 2.06 (1.11–4.53) | p = 0.0319 * | 0.128 | 0.0597 |
G-CSF | 15.29 (4.41–25.92) | 16.51 (3.62–28.34) | p = 0.198 | 0.0131 | 0.0102 |
PDGF | 0.00 (0.00–0.37) | 0.00 (0.00–0.52) | p = 0.254 | 0.131 | 0.115 |
VEGF | 4.03 (0.00–13.97) | 5.79 (0.00–50.29) | p = 0.0715 | 0.00988 | 0.00548 |
GG n = 88 (51.46%) | AG/AA n = 83 (48.53%) | p Value | ||
---|---|---|---|---|
Sex, F | N (%) | 57 (64.80) | 56 (67.50) | p = 0.710 |
Age, years | Mean, (SD) | 37.20 (12.38) | 34.27 (12.04) | p = 0.111 |
Disease duration, months | Median (IQR) | 6.66 (1.3–26.13) | 3.1 (0.90–24.60) | p = 0.227 |
EDSS | Median (IQR) | 2 (1–2.5) | 2 (1–2.25) | p = 0.647 |
OCB presence, yes | N (%) | 70/87 (80.50) | 62/79 (78.50) | p = 0.752 |
Radiological activity at diagnosis | N (%) | 28/86 (32.60) | 46/80 (57.50) | p = 0.001 * |
Clinical activity at diagnosis | N (%) | 34 (38.63) | 34 (40.96) | p = 0.707 |
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Bruno, A.; Dolcetti, E.; Azzolini, F.; Moscatelli, A.; Gambardella, S.; Ferese, R.; Rizzo, F.R.; Gilio, L.; Iezzi, E.; Galifi, G.; et al. Interleukin 6 SNP rs1818879 Regulates Radiological and Inflammatory Activity in Multiple Sclerosis. Genes 2022, 13, 897. https://doi.org/10.3390/genes13050897
Bruno A, Dolcetti E, Azzolini F, Moscatelli A, Gambardella S, Ferese R, Rizzo FR, Gilio L, Iezzi E, Galifi G, et al. Interleukin 6 SNP rs1818879 Regulates Radiological and Inflammatory Activity in Multiple Sclerosis. Genes. 2022; 13(5):897. https://doi.org/10.3390/genes13050897
Chicago/Turabian StyleBruno, Antonio, Ettore Dolcetti, Federica Azzolini, Alessandro Moscatelli, Stefano Gambardella, Rosangela Ferese, Francesca Romana Rizzo, Luana Gilio, Ennio Iezzi, Giovanni Galifi, and et al. 2022. "Interleukin 6 SNP rs1818879 Regulates Radiological and Inflammatory Activity in Multiple Sclerosis" Genes 13, no. 5: 897. https://doi.org/10.3390/genes13050897