Caucasians carriers of MTHFR A1298C polymorphism have a greater risk in developing multiple sclerosis: a meta-analysis of genetic association studies T. Koufakis 1,2 , I. Gabranis 2 , K. Karanikas 2 , G. Hadjigeorgiou 3 , E. Zintzaras 1,4 1 Department of Biomathematics, School of Medicine, University of Thessaly, Larissa, Greece 2 Department of Internal Medicine, General Hospital of Larissa, Larissa, Greece 3 Department of Neurology, School of Medicine, University of Thessaly, Larissa, Greece 4 Institute for Clinical Research and Health Policy Studies, Tufts University School of Medicine Boston, MA, USA Introduction and purpose: Multiple sclerosis (MS) is a chronic neurological disease characterized by central nervous system inflammation and demyelination of nerve axons (Image 1). The aim of this study was to investigate the relationship between two common polymorphisms in MTHFR gene and MS. Methods: We systematically searched Pubmed for all studies investigating the relationship between the MTHFR C677T and A1298C polymorphisms and the development of MS. The associations were indicated as odds ratios (ORs) with the corresponding 95% confidence interval (CI). The pooled OR was estimated using random effects model. The meta- analysis examined the contrast of TT homozygotes and CT heterozygotes (TT+CT) versus CC homozygotes (dominant genetic model). Heterogeneity between studies was tested using the Q-statistic, while the quality of the included studies was judged according to the compliance of genotype distribution in the control group with the Hardy- Weinberg Equilibrium (HWE). Results: 5 studies for C677T and 3 studies for A1298C met the meta-analysis inclusion criteria (Table 1). All studies were in HWE. Overall, the analysis failed to detect significant association between C677T {OR 0.94 with 95% CI (0.76-1.16)} and A1298C {OR 4.17 with 95% CI (0.87-20.36)} polymorphisms and MS. In an analysis of subgroups, the odds ratio were not significant for the Caucasian nor the Arab sample, regarding the association between C677T polymorphism and MS. Only in the Caucasian population was the A1298C association of marginal significance, with odds ratio 1.68 (1.08–2.62) (I 2 = 39%) (Graph 1). Image 1 The pathogenesis of MS (From Frohman et al. Nat Rev Neurol, 2013) 1 st Author, Year SNP Racial Descent Cases Controls Huang, 1997 C677T Caucasians 150 110 Tajouri, 2006 C677T Caucasians 101 101 Szvetko, 2007 A1298C Caucasians 130 131 Klotz, 2010 C677T & A1298C Caucasians 138 156 Alatab, 2011 C677T Arabs 194 230 Mrissa, 2013 C677T & A1298C Arabs 80 200 Table 1 Main characteristics of the studies included in the meta-analysis Graph 1 MTHFR polymorphisms and the risk of MS 1.68 (1.08-2.62) A1298C Caucasians Graph 2 Racial Descent of subjects included in the meta-analysis Arabs Caucasians C677T ALL A1298C ALL Conclusion: The meta-analysis results suggested that Caucasians carriers of A1298C polymorphism may have a greater genetic risk in developing MS. However, a greater number of studies and larger sample sizes are needed to establish the role of the MTHFR gene in the pathogenesis of MS. References 1. Zintzaras, Koufakis et al. Eur J Epidemiol, 2006 2. Hadjigeorgiou, Doxani et al. J Clin Pharm Ther, 2013 3. Huang, He et al. Eur J Neurol, 2007