Association between polymorphisms of a folate – homocysteine – methionine – SAM metabolising enzyme gene and multiple sclerosis in a Polish population
Abstract
Background and Objectives. Multiple sclerosis (MS) is a chronic inflammatory, autoimmune disease with a still unknown aetiology. The main initial mechanism of demyelination and injury to the central nervous system (CNS) appears to be inflammation. Neurotoxicity induced by homocysteine (Hcy) may be a factor affecting this process. 5,10-methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme involved in Hcy metabolism. It leads to Hcy remethylation to methionine. In the present study, we aimed to investigate a possible association between two variants of MTHFR gene in patients with MS in Poland and healthy individuals.
Methods. In this study, we genotyped 174 relapsing-remitting MS patients and 186 healthy controls using the TaqMan technique.
Results and Conclusions. It was found that, regardless of the presence of a specific allele, the gender of MS patients affects age at the time of the clinical onset of the disease: in rs1801133 for the C allele and T, the average age was 35 years for women and 29 for men (p = 0.0004; p = 0.034 respectively). Similarly for the second polymorphism rs1801131 for the A allele and C, the average age was 35 years for women and 29 for men (p = 0.001; p = 0.01 respectively). No significant allelic / genotypic frequency differences have been observed between the studied groups (c.677C > T, CT/TT p = 0.719, p = 0.262; c.1298A > C, AC/CC of p = 0.686; p = 0.66). We found no association between polymorphisms of a folate-homocysteine-methionine-SAM metabolising gene enzyme and multiple sclerosis in a Polish population.
Keywords: multiple sclerosispolymorphismMTHFR genefolate
References
- Surtees R, Leonard J, Austin S. Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet. 1991; 338(8782-8783): 1550–1554.
- Vrethem M, Mattsson E, Hebelka H, et al. Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler. 2003; 9(3): 239–245.
- Ramsaransing GSM, Fokkema MR, Teelken A, et al. Plasma homocysteine levels in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006; 77(2): 189–192.
- Kruman II, Culmsee C, Chan SL, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 2000; 20(18): 6920–6926.
- Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 1997; 94(11): 5923–5928.
- Klotz L, Farkas M, Bain N, et al. The variant methylenetetrahydrofolate reductase c.1298A>C (p.E429A) is associated with multiple sclerosis in a German case-control study. Neurosci Lett. 2010; 468(3): 183–185.
- Fekih Mrissa N, Mrad M, Klai S, et al. Association of methylenetetrahydrofolate reductase A1298C polymorphism but not of C677T with multiple sclerosis in Tunisian patients. Clin Neurol Neurosurg. 2013; 115(9): 1657–1660.
- Cevik B, Yigit S, Karakus N, et al. Association of methylenetetrahydrofolate reductase gene C677T polymorphism with multiple sclerosis in Turkish patients. J Investig Med. 2014; 62(8): 980–984.
- Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69(2): 292–302.
- Chambers J, Freeny A, Heiberger R. Analysis of Variance; Designed Experiments. Statistical Models in S. 2017: 145–193.
- Wilcoxon F. Individual Comparisons by Ranking Methods. Biometrics Bulletin. 1945; 1(6): 80.
- SHAPIRO SS, WILK MB. An analysis of variance test for normality (complete samples). Biometrika. 1965; 52(3-4): 591–611.
- Levene H. Robust tests for equality of variances. Contributions to Probability and Statistics: Essays in Honor of Harold Hotelling. Stanford University Press. ; 1960: 278–292.
- Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society: Series B (Methodological). 2018; 57(1): 289–300.
- Lydersen S, Fagerland MW, Laake P. Recommended tests for association in 2 x 2 tables. Stat Med. 2009; 28(7): 1159–1175.
- R Co. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. .. Foundation for Statistical Computing, Vienna, Austria. URL https://www R-project org. 2018.
- Thompson A, Baranzini S, Geurts J, et al. Multiple sclerosis. The Lancet. 2018; 391(10130): 1622–1636.
- Hadjigeorgiou GM, Kountra PM, Koutsis G, et al. Replication study of GWAS risk loci in Greek multiple sclerosis patients. Neurol Sci. 2019; 40(2): 253–260.
- Gil-Varea E, Urcelay E, Vilariño-Güell C, et al. Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course. J Neuroinflammation. 2018; 15(1): 265.
- Simsek H, Geckin H, Sensoz NP, et al. Association Between IL7R Promoter Polymorphisms and Multiple Sclerosis in Turkish Population. J Mol Neurosci. 2019; 67(1): 38–47.
- Wawrusiewicz-Kurylonek N, Chorąży M, Posmyk R, et al. The FOXP3 rs3761547 Gene Polymorphism in Multiple Sclerosis as a Male-Specific Risk Factor. Neuromolecular Med. 2018; 20(4): 537–543.
- Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain. 2006; 129(Pt 3): 595–605.
- Harbo HF, Gold R, Tintoré M. Sex and gender issues in multiple sclerosis. Ther Adv Neurol Disord. 2013; 6(4): 237–248.
- Szvetko AL, Fowdar J, Nelson J, et al. No association between MTHFR A1298C and MTRR A66G polymorphisms, and MS in an Australian cohort. J Neurol Sci. 2007; 252(1): 49–52.
- Lee YHo, Seo YHo, Kim JH, et al. Meta-analysis of associations between MTHFR and GST polymorphisms and susceptibility to multiple sclerosis. Neurol Sci. 2015; 36(11): 2089–2096.
![](https://journals.viamedica.pl/plugins/generic/popups/images/icons/close.png)