Abstract
Both genetic and inflammatory factors are suspected in the etiology of multiple sclerosis (MS). Of genetic factors, the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been associated with increased levels of plasma homocysteine, a neuronal excitotoxic amino acid. Sclerotic patients also have elevated levels of plasma and CSF homocysteine. In this study, the association between C677T polymorphism and MS was tested by recruiting 230 healthy and 194 multiple sclerotic age- and gender-matched patients. The MTHFR C677T polymorphism and the serum levels of inflammatory mediators IL-1β, TNFα, and CRP were measured. TNFα, CRP, and IL-1β levels were significantly higher in sclerotic patients. T allele was 1.7 times more present in this group. In patient’s group, the levels of all inflammatory mediators were higher in T/T compared to two other genotypes. Evaluation of the age of onset of disease revealed that subjects with T allele developed the MS disease, almost 4 years sooner than other genotype. We concluded that having T allele of C677T in MS might be accompanied with higher levels of serum inflammatory mediators and a vulnerability to earlier age of onset of disease. Further studies are needed to elucidate the underlying mechanisms.
References
Bagley PJ, Selhub J (1998) A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci USA 95:13217–13220
Baranzini SE, Wang J, Gibson RA et al (2009) Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet 18:767–778
Chawla RK, Watson WH, Eastin CE, Lee EY, Schmidt J, Mc Clain CJ (1998) S-adenosylmethionine deficiency and TNF-alpha in lipopolysaccharide-induced hepatic injury. Am J Physiol 275:G125–129
Compston A, Coles A (2008) Multiple sclerosis. Lancet 372(9648):1502–1517
Cornacchia E, Golbus J, Maybaum J, Strahler J, Hanash S, Richardson B (1988) Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. Journal of Immunology 140:2197–2200
Etemadifar M, Janghorbani M, Shaygannejad V, Ashtari F (2006) Prevalence of multiple sclerosis in Isfahan, Iran. Neuroepidemiology 27:39–44
Ewing C, Bernard CCA (1998) Insights into the aetiology and pathogenesis of multiple sclerosis. Immunol Cell Biol 76:47–54
Freedman MS (2006) Disease-modifying drugs for multiple sclerosis current and future aspect. Expert Opin Pharmacother 7:S1–S92
Friso S, Choi SW, Girelli D et al (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA 99:5606–5611
Frosst P, Blom HJ, Milos R et al (1995) A candidate genetic risk factor for vascular disease. A common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113
Giovannoni G, Thorpe JW, Kidd D et al (1996) Soluble E-selectin in multiple sclerosis: raised concentrations in patients with primary progressive disease. J Neurol Neurosurg Psychiatry 60:20–26
Giovannoni G, Miller DH, Losseff NA et al (2001) Serum inflammatory markers and clinical/MRI markers of disease progression in multiple sclerosis. J Neurol 248:487–495
Goyette P, Sumner JS, Milos R et al (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7:195–200
Haines JL, Ter-Minassian M, Bazyk A et al (1996) A complete genomic screen for multiple sclerosis underscores a role for the major histocompatibility complex. Nat Genet 13:469–471
Jonasdottir A, Thorlacius T, Fossdal R et al (2003) A whole genome association study in Icelandic multiple sclerosis patients with 4804 markers. J Neuroimmunol 143:88–92
Kalanie H, Kamgooyan M, Sadeghian H, Kalanie AR (2000) Histocompatibility antigen association with multiple sclerosis in Iran. Mult Scler 6:317–319
Klotz L, Farkas M, Bain N et al (2010) The variant methylenetetrahydrofolate reductase c.1298A>C (p.E429A) is associated with multiple sclerosis in a German case–control study. Neurosci Lett 468:183–185
Kohara K, Fujisawa M, Ando F et al (2003) MTHFR gene polymorphism as a risk factor for silent brain infarcts and white matter lesions in the Japanese general population: the NILS-LSA study. Stroke 34:1130–1135
Lin JJ, Yueh KC, Liu CS, Liu JT, Lin SZ (2007) 5,10-Methylenetetrahydrofolate reductase C677T gene polymorphism can influence age at onset of Parkinson’s disease. Acta Neurol Taiwan 16:150–157
Mager A, Koren-Morag N, Shohat M, Harell D, Battler A (2005) Family history, plasma homocysteine, and age at onset of symptoms of myocardial ischemia in patients with different methylenetetrahydrofolate reductase genotypes. Am J Cardiol 95:1420–1424
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–952
Purohit V, Abdelmalek MF, Barve S et al (2007) Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium1, 2, 3, 4. Am J Clin Nutr 86:14–24
Ramsaransing GS, Fokkema MR, Teelken A, Arutjunyan AV, Koch M, De Keyser J (2006) Plasma homocysteine levels in multiple sclerosis. J Neurol Neurosurg Psychiatry 77:189–192
Rosati G (2001) The prevalence of multiple sclerosis in the world: an update. Neurol Sci 22:117–139
Sadovnick AD, Armstrong H, Rice GP et al (1993) A population-based study of multiple sclerosis in twins: update. Ann Neurol 33:281–285
Soilu-Hänninen M, Koskinen JO, Laaksonen M, Hänninen A, Lilius EM, Waris M (2005) High sensitivity measurement of CRP and disease progression in multiple sclerosis. Neurology 65:153–155
Song Z, Barve S, Chen T et al (2003) S-adenosylmethionine (AdoMet) modulates endotoxin stimulated interleukin-10 production in monocytes. Am J Physiol Gastrointest Liver Physiol 284:G949–G955
Surtees R, Leonard J, Austin S (1991) Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 338:1550–1554
Tajouri L, Martin V, Gasparini C et al (2006) Genetic investigation of methylenetetrahydrofolate reductase (MTHFR) and catechol-O-methyl transferase (COMT) in multiple sclerosis. Brain Res Bull 69:327–331
Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE (2001) Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 22:195–201
Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64:169–172
Acknowledgment
This work was supported by a research grant from Endocrinology and Metabolism Research Center of the Tehran University of Medical Sciences. The authors would like to thank the staff of bio-nanotechnology’s laboratory for their technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Alatab, S., Hossein-nezhad, A., Mirzaei, K. et al. Inflammatory Profile, Age of Onset, and the MTHFR Polymorphism in Patients with Multiple Sclerosis. J Mol Neurosci 44, 6–11 (2011). https://doi.org/10.1007/s12031-010-9486-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-010-9486-y