Association Study between Functional Polymorphisms of MMP9 Gene Promoter and Multiple Sclerosis Susceptibility in an Iranian Population
Background: Matrix metalloproteinase-9 (MMP-9) polymorphisms, C−1562 T and -90 (CA) n repeats, which influence transcriptional activity of this gene, are proposed to play a role in MS susceptibility and its development. In the present study, the possible association of MMP-9 polymorphisms in Iranian MS patients is studied.
Methods: Association of MMP-9 mentioned gene polymorphisms with MS susceptibility was evaluated in unrelated Iranian subjects referred to Al-Zahra Hospital, Isfahan, Iran during 2014 to 2017.
Results: -1562 T allele of MMP-9 was associated with increased MS risk. However, we found no overall significant effect of −90 (CA)n repeat on MS susceptibility.
Conclusion: For as much as MMP-9 molecule is a potential target for MS therapy, to determine whether any of MMP-9 polymorphisms influence MS susceptibility in Iranian MS patients or not, concerning the significant influence of T allele on MS susceptibility and the non-significant association regarding CA repeats, further research is needed before proposing any definite conclusion.
2. Stephen S, Robin J MF, Maria B (2014). Multiple sclerosis genetics. Lancet Neurol, 13:700-709.
3. Brosnan CF, Raine CS (1996). Mechanisms of Immune Injury in Multiple Sclerosis. Brain Pathol, 6:243-257.
4. Dehghani L, Meamar R, Etemadifar M et al (2013). Can Vitamin D Suppress Endothelial Cells Apoptosis in Multiple Sclerosis Patients? Int J Prev Med, 4:S211-S215.
5. Waubant E (2006). Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis. Dis Markers, 22:235–244.
6. Yong VW, Power C, Forsyth P, Edwards DR (2001). Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci, 2:502-511.
7. Woessner JF Jr (1991). Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J, 5:2145-2154.
8. Chandler S, Coatesb R, Gearinga A et al (1995). Matrix metalloproteinases degrade myelin basic protein. Neurosci Lett, 21:223–226.
9. Gijbels K, Proost P, Masure S, Carton H, Billiau A, Opdenakker G (1993). Gelatinase B is present in the cerebrospinal fluid during experimental autoimmune encephalomyelitis and cleaves myelin basic protein. J Neurosci Res, 36:432-40.
10. Proost P, Vandamme J, Opdenakker G (1993). Leukocyte gelatinase B cleavage releases encephalitogens from human myelin basic protein. Biochem Biophys Res Commun, 192:1175-1181.
11. Gijbels K, Masure S, Carton H, Opdenakker G (1992). Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological disorders. J Neuroimmunol, 41:29-34.
12. Paemen L, Olsson T, Söderström M et al (1994). Evaluation of gelatinases and IL‐6 in the cerebrospinal fluid of patients with optic neuritis, multiple sclerosis and other inflammatory neurological diseases. Eur J Neurol, 1:55-63.
13. Comabella M, Río J, Espejo C et al (2009). Changes in matrix metalloproteinases and their inhibitors during interferon-beta treatment in multiple sclerosis. Clin Immunol, 130:145-150.
14. Benešová Y, Vašků A, Novotná H, Litzman J et al (2009). Matrix metalloproteinase-9 and matrix metalloproteinase-2 as biomarkers of various courses in multiple sclerosis. Mult Scler, 15(3)316-:22.
15. Fernandes KSS, Brum DG, Sandrim VC et al (2009). Matrix metalloproteinase-9 genotypes and haplotypes are associated with multiple sclerosis and with the degree of disability of the disease. J Neuroimmunol, 214:128-131.
16. La Russa A, Cittadella R, De Marco EV et al (2010). Single nucleotide polymorphism in the MMP-9 gene is associated with susceptibility to develop multiple sclerosis in an Italian case-control study. J Neuroimmunol, 225:175–179.
17. Shimajiri S, Arima N, Tanimoto A et al (1999). Shortened microsatellite d (CA) 21 sequence down-regulates promoter activity of matrix metalloproteinase 9 gene. FEBS Lett, 455:70-74.
18. Zhang B, Ye S, Herrmann S-M, Eriksson P et al (1999). Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation, 99:1788-1794.
19. Fiotti N, Zivadinov R, Altamura N et al (2004). MMP-9 microsatellite polymorphism and multiple sclerosis. J Neuroimmunol, 152:147–153
20. Peters DG, Kassam A, Jean PLS (1999). Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysm. Stroke, 30:2612-2616.
21. Zhang B, Henney A, Eriksson P et al (1999). Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12. 2–13.1. Hum Genet, 105:418-423.
22. Fernandes KSdS, Brum DG, Palei AC (2012). Functional MMP-9 polymorphisms modulate plasma MMP-9 levels in multiple sclerosis patients. J Neuroimmunol, 249:56–59
23. Waubant E, Goodkin D, Gee L, Bacchetti P et al (1999). Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis. Neurology, 53:1397-1401.
24. Nelissen I, Vandenbroeck K, Fiten P (2000). Polymorphism analysis suggests that the gelatinase B gene is not a susceptibility factor for multiple sclerosis. J Neuroimmunol, 105:58-63.
25. Yoon S, Tromp G, Vongpunsawad S (1999). Genetic analysis of MMP3, MMP9, and PAI-1 in Finnish patients with abdominal aortic or intracranial aneurysms. Biochem Biophys Res Commun, 265:563-568.
26. Benešová' Y, Vašků A, Štourač P (2008). Matrix metalloproteinase-9 and matrix metalloproteinase-2 gene polymorphisms in multiple sclerosis. J Neuroimmunol, 205:105–109.
27. Nischwitz S, Wolf C, Andlauer T et al (2015). MS susceptibility is not affected by single nucleotide polymorphisms in the MMP9 gene. J Neuroimmunol, 279:46–49
28. Živković M, Djurić T, Dinčić E (2007). Matrix metalloproteinase-9− 1562 C/T gene polymorphism in Serbian patients with multiple sclerosis. J Neuroimmunol, 189:147–150.
29. Jing L, Shuang -YL, Yan-Bo L et al (2017). Association Study of MMP-9 1562C/T Gene Polymorphism with Susceptibility to Multiple Autoimmune Diseases: A Meta-analysis. Arch Med Res, 48:105-112.