Polymorphisms of serotonin transporter gene and psychological status in patients with multiple sclerosis
Background: Multiple sclerosis (MS) is the most common neuroinflammatory disease in young adults. Anxiety and depression may predispose individuals to MS and flare-ups. Serotonin transmission is modified in some brain regions of patients with MS, and these changes may contribute to their psychiatric abnormalities. We studied the frequencies of common polymorphisms of the serotonin reuptake transporter (SERT) gene in patients with MS according to their psychological status.
Methods: The 5-HTTLPR, rs25531, and STin2VNTR polymorphisms of the SERT gene were genotyped by polymerase chain reaction (PCR)-based methods in 100 patients with MS and 100 healthy controls.
Results: There were no remarkable differences in SERT gene polymorphisms between patients with MS and healthy controls. Unlike the control group, 41% of the patients showed some degree of depression based on Beck Depression Inventory (BDI), but no association was observed between SERT gene polymorphisms after the patients were stratified by depression status.
Conclusion: In addition to SERT gene polymorphisms, modulation of serotonin at the synapses may also be regulated by genetic variations in tryptophan hydroxylase type 2 and serotonin receptors. Further studies with functional brain imaging of the serotonergic system in patients with MS can provide information on the role of serotonin in this disease.
2. Farjam M, Zhang GX, Ciric B, Rostami A. Emerging immunopharmacological targets in multiple sclerosis. J Neurol Sci 2015; 358(1-2): 22-30.
3. Bashinskaya VV, Kulakova OG, Boyko AN, Favorov AV, Favorova OO. A review of genome-wide association studies for multiple sclerosis: Classical and hypothesis-driven approaches. Hum Genet 2015; 134(11-12): 1143-62.
4. Farjam M, Beigi Zarandi FB, Farjadian S, Geramizadeh B, Nikseresht AR, Panjehshahin MR. Inhibition of NR2Bcontaining N-methyl-D-aspartate receptors (NMDARs) in experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Iran J Pharm Res 2014; 13(2): 695-705.
5. Shi J, Baxter LC, Kuniyoshi SM. Pathologic and imaging correlates of cognitive deficits in multiple sclerosis: Changing the paradigm of diagnosis and prognosis. Cogn Behav Neurol 2014; 27(1): 1-7.
6. Fragoso YD, Adoni T, Anacleto A, da Gama PD, Goncalves MV, Matta AP, et al. Recommendations on diagnosis and treatment of depression in patients with multiple sclerosis. Pract Neurol 2014; 14(4): 206-9.
7. Paparrigopoulos T, Ferentinos P, Kouzoupis A, Koutsis G, Papadimitriou GN. The neuropsychiatry of multiple sclerosis: focus on disorders of mood, affect and behaviour. Int Rev Psychiatry 2010; 22(1): 14-21.
8. Brenner P, Alexanderson K, Bjorkenstam C, Hillert J, Jokinen J, Mittendorfer-Rutz E, et al. Psychiatric diagnoses, medication and risk for disability pension in multiple sclerosis patients; a population-based register study. PLoS One 2014; 9(8): e104165.
9. Schumann R, Adamaszek M, Sommer N, Kirkby KC. Stress, depression and antidepressant treatment options in patients suffering from multiple sclerosis. Curr Pharm Des 2012; 18(36): 5837-45.
10. Araragi N, Lesch KP. Serotonin (5-HT) in the regulation of depression-related emotionality: Insight from 5-HT transporter and tryptophan hydroxylase-2 knockout mouse models. Curr Drug Targets 2013; 14(5): 549-70.
11. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274(5292): 1527-31.
12. Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, et al. Serotonin transporter promoter gain-offunction genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 2006; 78(5): 815-26.
13. Lovejoy EA, Scott AC, Fiskerstrand CE, Bubb VJ, Quinn JP. The serotonin transporter intronic VNTR enhancer correlated with a predisposition to affective disorders has distinct regulatory elements within the domain based on the primary DNA sequence of the repeat unit. Eur J Neurosci 2003; 17(2): 417-20.
14. Hofstetter HH, Mossner R, Lesch KP, Linker RA, Toyka KV, Gold R. Absence of reuptake of serotonin influences susceptibility to clinical autoimmune disease and neuroantigen-specific interferon-gamma production in mouse EAE. Clin Exp Immunol 2005; 142(1): 39-44.
15. Hesse S, Moeller F, Petroff D, Lobsien D, Luthardt J, Regenthal R, et al. Erratum to: Altered serotonin transporter availability in patients with multiple sclerosis.European Eur J Nucl Med Mol Imaging 2014; 41(8): 1640-1.
16. Hesse S, Moeller F, Petroff D, Lobsien D, Luthardt J, Regenthal R, et al. Altered serotonin transporter availability in patients with multiple sclerosis. Eur J Nucl Med Mol Imaging 2014; 41(5): 827-35.
17. Taler M, Gil-Ad I, Korob I, Weizman A. The immunomodulatory effect of the antidepressant sertraline in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Neuroimmunomodulation 2011; 18(2): 117-22.
18. Mostert JP, Admiraal-Behloul F, Hoogduin JM, Luyendijk J, Heersema DJ, van Buchem MA, et al. Effects of fluoxetine on disease activity in relapsing multiple sclerosis: a double-blind, placebo-controlled, exploratory study. J Neurol Neurosurg Psychiatry 2008; 79(9): 1027-31.
19. Mitsonis CI, Zervas IM, Potagas CM, Mitropoulos PA, Dimopoulos NP, Sfagos CA, et al. Effects of escitalopram on stress-related relapses in women with multiple sclerosis: an open-label, randomized, controlled, one-year follow-up study. Eur Neuropsychopharmacol 2010; 20(2): 123-31.
20. Foley P, Lawler A, Chandran S, Mead G. Potential disease-modifying effects of selective serotonin reuptake inhibitors in multiple sclerosis: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2014; 85(6): 709-10.
21. Kang H, Metz LM, Traboulsee AL, Eliasziw M, Zhao GJ, Cheng Y, et al. Application and a proposed modification of the 2010 McDonald criteria for the diagnosis of multiple sclerosis in a Canadian cohort of patients with clinically isolated syndromes. Mult Scler 2014; 20(4): 458-63.
22. Ghassemzadeh H, Mojtabai R, Karamghadiri N, Ebrahimkhani N. Psychometric properties of a Persian-language version of the Beck Depression Inventory--Second edition: BDI-II-PERSIAN. Depress Anxiety 2005; 21(4): 185-92.
23. Farjadian S, Fakhraei B, Moeini M, Nasiri M, Fattahi MR. Serotonin transporter gene polymorphisms in Southwestern Iranian patients with irritable bowel syndrome. Arab J Gastroenterol 2013; 14(2): 59-62.
24. Farjadian S, Moghtaderi M, Fakhraei B, Nasiri M, Farjam M. Association between serotonin transporter gene polymorphisms and childhood asthma. J Asthma 2013; 50(10): 1031-5.
25. Kaiser R, Muller-Oerlinghausen B, Filler D, Tremblay PB, Berghofer A, Roots I, et al. Correlation between serotonin uptake in human blood platelets with the 44-bp polymorphism and the 17-bp variable number of tandem repeat of the serotonin transporter. Am J Med Genet 2002; 114(3): 323-8.
26. Pytliak M, Vargova V, Mechirova V, Felsoci M. Serotonin receptors - from molecular biology to clinical applications. Physiol Res 2011; 60(1): 15-25.
27. Murphy DL, Lerner A, Rudnick G, Lesch KP. Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol Interv 2004; 4(2): 109-23.
28. Nemeroff CB, Owens MJ. The role of serotonin in the pathophysiology of depression: as important as ever. Clin Chem 2009; 55(8): 1578-9.
29. Starr LR, Hammen C, Brennan PA, Najman JM. Relational security moderates the effect of serotonin transporter gene polymorphism (5-HTTLPR) on stress generation and depression among adolescents. J Abnorm Child Psychol 2013; 41(3): 379-88.
30. Saul A, Taylor B, Simpson S Jr, Ponsonby AL, Blizzard L, Dwyer T, et al. Polymorphism in the serotonin transporter gene polymorphisms (5-HTTLPR) modifies the association between significant life events and depression in people with multiple sclerosis. Mult Scler 2018. [Epub ahead of print].
31. Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev 2008; 13(3): 216-26.
32. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010; 464(7285): 104-7.
33. Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 2014; 10(4): 225-38.
34. Kingwell E, Marriott JJ, Jette N, Pringsheim T, Makhani N, Morrow SA, et al. Incidence and prevalence of multiple sclerosis in Europe: A systematic review. BMC Neurol 2013; 13: 128.
35. Farjam M, Ebrahimpour A, Fakhraei B. CD21 positive B cell: A novel target for treatment of multiple sclerosis. Med Hypotheses 2013; 80(5): 556-7.
36. Vojdani A. A potential link between environmental triggers and autoimmunity. Autoimmune Diseases 2014; 2014: 437231.
37. Kucukali CI, Kurtuncu M, Coban A, Cebi M, Tuzun E. Epigenetics of multiple sclerosis: An updated review. Neuromolecular Med 2015; 17(2): 83-96.
38. Hamon M, Blier P. Monoamine neurocircuitry in depression and strategies for new treatments. Prog neuropsychopharmacol Biol Psychiatry 2013; 45: 54-63.