The MTHFR enzyme converts synthetic folic acid and dietary folate into its active form, L-methylfolate, which plays a critical role in neurotransmitter synthesis.1 Some individuals carry a mutation at the C677T SNP of the MTHFR gene, which results in 45% reduction in activity for heterozygotes (C/T) and a 70% reduction in activity for homozygotes (T/T).2 Individuals who carry this mutation will have a reduced capacity to create L-methylfolate.2 A second polymorphism, the A1298C SNP, has also been suggested to have an impact on serum folate levels.1 A literature review was undertaken to examine the clinical significance of this polymorphism.
Of the 21 publications that examined the A1298C SNP singly 3–23, only 1 showed a significant effect of the polymorphism3. Of the 17 publications that examined the C667T/A1298C haplotype 9-25, only 3 showed a significant effect of the 677CT/1298AC haplotype on serum folate levels14,18,25, while 3 showed trending or mixed results 11,16,22. The largest positive study (n = 10,601) showed a ~3-5% decrease in serum folate levels for CT/AC individuals relative to the CT/AA individuals.25 Although the finding in this one study is statistically significant, a 3-5% decrease in serum folate is unlikely to be clinically significant,
particularly when weighed against the effect of the C677T SNP on folate metabolism (up to 70% reduced).1
At this time, the MTHFR A1298C polymorphism in isolation shows little to no impact on folate levels in multiple peer-reviewed publications (20/21 negative studies). Haplotype analyses of this SNP in combination with the C677T SNP are inconsistent (11/17 negative studies) and suggest a very modest, if any, impact of the double heterozygous stateindependent of the effect of the C677T polymorphism.
The MTHFR A1298C polymorphism has not demonstrated clinical significance.
The search was conducted within the PubMed database. Results were limited to English studies that reported serum, plasma, or red blood cell (RBC) folate levels. Studies with a sample size of less than 100 individuals were excluded.Because the A1298C SNP has been hypothesized to modulate clinical effects in C677T heterozygotes, the analysis was conducted by reviewing the A1298C SNP both singly and in haplotype (i.e. in combination with C677T). After redundant and irrelevant studies were eliminated, a total of 21 publications (n = 24,176) entered the single genotype review3-23 and 17 publications (n = 18,052) entered the haplotype review9-25.
1. Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014;533(1):11-20. doi:10.1016/j.gene.2013.09.063.
2. Nelson JC. The evolving story of folate in depression and the therapeutic potential of l-methylfolate. Am J Psychiatry. 2012;169(12):1223-5. doi:10.1176/appi.ajp.2012.12091207.
3. Fredriksen A, Meyer K, Ueland PM, Vollset SE, Grotmol T, Schneede J. Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism. Hum Mutat. 2007;28(9):856-65. doi:10.1002/humu.20522.
4. DeVos L, Chanson A, Liu Z. Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations. Am J …. 2008;88(58):1149-1158. Available at: https://ajcn.nutrition.org/content/88/4/1149.short. Accessed May 27, 2014.
5. Hazra A, Kraft P, Lazarus R, et al. Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway. Hum Mol Genet. 2009;18(23):4677-87. doi:10.1093/hmg/ddp428.
6. Semmler A, Moskau-Hartmann S, Stoffel-Wagner B, Elger C, Linnebank M. Homocysteine plasma levels in patients treated with antiepileptic drugs depend on folate and vitamin B12 serum levels, but not on genetic variants of homocysteine metabolism. Clin Chem Lab Med. 2013;51(3):665-9. doi:10.1515/cclm-2012-0580.
7. Van Winkel R, Rutten BP, Peerbooms O, Peuskens J, van Os J, De Hert M. MTHFR and risk of metabolic syndrome in patients with schizophrenia. Schizophr Res. 2010;121(1-3):193-8. doi:10.1016/j.schres.2010.05.030.
8. Vollset SE, Igland J, Jenab M, et al. The association of gastric cancer risk with plasma folate, cobalamin, and methylenetetrahydrofolate reductase polymorphisms in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev. 2007;16(11):2416-24. doi:10.1158/1055-9965.EPI-07-0256.
9. Aléssio ACM, Annichino-Bizzacchi JM, Bydlowski SP, Eberlin MN, Vellasco AP, Höehr NF. Polymorphisms in the methylenetetrahydrofolate reductase and methionine synthase reductase genes and homocysteine levels in Brazilian children. Am J Med Genet A. 2004;128A(3):256-60. doi:10.1002/ajmg.a.30108.
10. Bailey LB, Duhaney RL, Maneval DR, et al. Vitamin B-12 status is inversely associated with plasma homocysteine in young women with C677T and/or A1298C methylenetetrahydrofolate reductase polymorphisms. J Nutr. 2002;132(7):1872-8. Available at: https://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:Human+Nutrition+and+Metabolism+Vitamin+B-12+Status+Is+Inversely+Associated+with+Plasma+Homocysteine+in+Young+Women+with+C677T+and+/+or+A1298C+Methylenetetrahydrofolate#4. Accessed May 27, 2014.
11. Chango A, Potier De Courcy G, Boisson F, et al. 5,10-methylenetetrahydrofolate reductase common mutations, folate status and plasma homocysteine in healthy French adults of the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) cohort. Br J Nutr. 2000;84(6):891-6. Available at: https://journals.cambridge.org/abstract_S0007114500002518. Accessed May 27, 2014.
12. Dekou V, Whincup P, Papacosta O, et al. The effect of the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women from the British regional heart study. Atherosclerosis. 2001;154(3):659-66. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11257267.
13. Devlin AM, Clarke R, Birks J, Evans JG, Halsted CH. Interactions among polymorphisms in folate-metabolizing genes and serum total homocysteine concentrations in a healthy elderly population. Am J Clin Nutr. 2006;83(3):708-13. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16522921.
14. Födinger M, Buchmayer H, Heinz G, et al. Effect of MTHFR 1298A–>C and MTHFR 677C–>T genotypes on total homocysteine, folate, and vitamin B(12) plasma concentrations in kdiney graft recipients. J Am Soc Nephrol. 2000;11(10):1918-25. Available at: https://jasn.asnjournals.org/content/11/10/1918.short. Accessed May 13, 2014.
15. Friedman G, Goldschmidt N, Friedlander Y, et al. A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr. 1999;129(9):1656-61. Available at: https://jn.nutrition.org/content/129/9/1656.short. Accessed May 13, 2014.
16. Lachmeijer AM a., Arngrímsson R, Bastiaans EJ, et al. Mutations in the gene for methylenetetrahydrofolate reductase, homocysteine levels, and vitamin status in women with a history of preeclampsia. Am J Obstet Gynecol. 2001;184(3):394-402. doi:10.1067/mob.2001.109393.
17. Lee YS, Han DH, Jeon CM, et al. Serum homocysteine, folate level and methylenetetrahydrofolate reductase 677, 1298 gene polymorphism in Korean schizophrenic patients. Neuroreport. 2006;17(7):743-6. doi:10.1097/01.wnr.0000215777.99473.52.
18. Mahfouz R a, Cortas NK, Charafeddine KM, et al. Correlation of methylenetetrahydrofolate reductase polymorphisms with homocysteine metabolism in healthy Lebanese adults. Gene. 2012;504(2):175-80. doi:10.1016/j.gene.2012.05.029.
19. Ozarda Y, Sucu DK, Hizli B, Aslan D. Rate of T alleles and TT genotype at MTHFR 677C->T locus or C alleles and CC genotype at MTHFR 1298A->C locus among healthy subjects in Turkey: impact on homocysteine and folic acid status and reference intervals. Cell Biochem Funct. 2009;27(8):568-77. doi:10.1002/cbf.1610.
20. Parle-McDermott A, Mills JL, Molloy AM, et al. The MTHFR 1298CC and 677TT genotypes have opposite associations with red cell folate levels. Mol Genet Metab. 2006;88(3):290-4. doi:10.1016/j.ymgme.2006.02.011.
21. Roffman JL, Weiss AP, Purcell S, et al. Contribution of methylenetetrahydrofolate reductase (MTHFR) polymorphisms to negative symptoms in schizophrenia. Biol Psychiatry. 2008;63(1):42-8. doi:10.1016/j.biopsych.2006.12.017.
22. Van der Put NM, Gabreëls F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62(5):1044-51. doi:10.1086/301825.
23. Vaughn JD, Bailey LB, Shelnutt KP, et al. Methionine synthase reductase 66A->G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous methylenetetrahydrofolate reductase 677C->T variant. J Nutr. 2004;134(11):2985-90. Available at: https://nutrition.highwire.org/content/134/11/2985.short. Accessed May 27, 2014.
24. Guéant-Rodriguez R-M, Guéant J-L, Debard R, et al. Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations. Am J Clin Nutr. 2006;83(3):701-7. Available at: https://ajcn.nutrition.org/content/83/3/701.short. Accessed May 13, 2014.
25. Ulvik A, Ueland PM, Fredriksen A, et al. Functional inference of the methylenetetrahydrofolate reductase 677C > T and 1298A > C polymorphisms from a large-scale epidemiological study. Hum Genet. 2007;121(1):57-64. doi:10.1007/s00439-006-0290-2.