HomeClinical White PapersWhat is the clinical significance of the MTHFR A1298C polymorphism? What is the clinical significance of the MTHFR A1298C polymorphism? November 30, 2018Clinical White Papers What is MTHFR? The methylenetetrahydrofolate reductase (MTHFR) enzyme converts synthetic folic acid and dietary folate into its active form, L-methylfolate, which plays a critical role in neurotransmitter synthesis. Some individuals carry a mutation at the C677T SNP of the MTHFR gene, which results in about a 35% reduction in activity for heterozygotes (C/T) and about a 70% reduction in activity for homozygotes (T/T).1,2 Individuals who carry this mutation will have a reduced capacity to create L-methylfolate. A second polymorphism, the A1298C SNP, has also been suggested to have an impact on MTHFR enzyme activity.2-5 What is the effect of the MTHFR A1298C polymorphism on MTHFR enzyme activity? The MTHFR A1298C polymorphism reduces MTHFR enzyme activity to a lesser extent than the MTHFR C677T polymorphism.2-4 Table 1 summarizes the enzyme activities for the MTHFR C667T/A1298C haplotype from three studies.2-4 The studies were fairly small, and the largest study yielded the smallest effect.3 It is hypothesized that the MTHFR C677T polymorphism may have a larger effect on MTHFR enzyme activity because of its location within the catalytic region rather than the regulatory domain.4 Therefore, since the variability in MTHFR enzyme activity is not as large as with the C677T polymorphism (up to 70% reduction), testing for MTHFR A1298C does not seem to be clinically useful at this time. Table 1: The Effect of the MTHFR C677T and A1298C Polymorphisms on MTHFR Enzyme Activity Genotype 677CC 677CT 677TT 1298 AA 100% 51-73%2-4 22-32%2-4 1298 AC 60-92%2-4 36-60%2-4 N/A 1298 CC 52-60%2-4 N/A N/A *Percentages denote MTHFR enzyme activity. Ranges are included to reflect different values reported in the literature. Does MTHFR genotype affect response to L-methylfolate in depressed patients? At this time, only one study has evaluated the MTHFR A1298C and C677T genotypes in depressed patients taking L-methylfolate supplementation.6 This study found no significant improvement on the 28-Item Hamilton Depression Rating Scale (HDRS-28) for the MTHFR AC/CC genotype group compared to the wild-type (A/A) genotype. While the results were also not significant for the MTHFR C677T genotype, there was a trend for CT/TT patients benefiting more from L-methylfolate supplementation. When additional depression scales were analyzed, significant results were obtained for the CT/TT genotype group for the Clinical Global Impressions-Severity of Illness (CGI-S) scale and the Cognitive and Physical Functioning Questionnaire (CPFQ), but not the 7-Item Hamilton Depression Rating Scale (HDRS-7). However, the MTHFR A1298C genotype did not significantly affect outcome on any scale. The major limitation of this study was its small sample size. More research needs to be done to determine the effect of MTHFR genotype on response to L-methylfolate supplementation in depressed patients. References 1. Frosst, P. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10, 111-113, doi:10.1038/ng0595-111 (1995). 2. Chango, A. et al. The effect of 677C—>T and 1298A—>C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects. Br J Nutr 83, 593-596 (2000). 3. van der Put, N. M. et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62, 1044-1051, doi:10.1086/301825 (1998). 4. Weisberg, I., Tran, P., Christensen, B., Sibani, S. & Rozen, R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64, 169-172, doi:10.1006/mgme.1998.2714 (1998). 5. Lievers, K. J. et al. A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. J Mol Med (Berl) 79, 522-528, doi:10.1007/s001090100253 (2001). 6. Papakostas, G. I. et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J Clin Psychiatry 75, 855-863, doi:10.4088/JCP.13m08947 (2014). Patient BIPOC (formerly Minority) Mental Health Month: Breaking Stigma, Building Trust Despite many efforts to stem it, stigma around mental health still exists, particularly in BIPOC (Black, Indigenous, and People of Color) communities. July mark... 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Patient BIPOC (formerly Minority) Mental Health Month: Breaking Stigma, Building Trust Despite many efforts to stem it, stigma around mental health still exists, particularly in BIPOC (Black, Indigenous, and People of Color) communities. July mark... Read more
Patient Long-Term Effects of Antidepressants: What Research Shows Anyone who’s ever taken antidepressants for an extended period of time has probably wondered whether they’ll experience long-term effects: After years ... Read more
Patient Have a Mindful Summer: Take a Breather with These Simple Exercises Summer is a great time to kick back and relax—if you can find the time. Managing the hustle and bustle of kids off school, planning for fun summer activities an... Read more
Patient Which Mental Health Provider Should I Consider? A Symptom-Based Guide The support of a good healthcare provider can make all the difference when you’re struggling with your mental health. But how do you connect to one in a sea of ... Read more
Patient One explanation for why we experience Side Effects? Understanding Your Genetic Response to Antidepressants Antidepressants often play an essential role in helping patients with their mental health conditions. But as many patients can attest, it’s frustrating when... Read more
Patient Barriers at Every Turn: How Systemic and Social Factors Block Men from Mental Health Care Taking the important step of seeking care for mental health isn’t always an easy decision. Uncertainty about the need for care, social stigmas associated wi... Read more
Healthcare Provider Overcoming Side Effect Concerns: Leveraging Pharmacogenomic Insights to Inform Depression and Anxiety Medication Selection Whitnee Brown, a lifelong resident now practicing in Birmingham, Alabama has nearly an entire alphabet following her name, abbreviations for degrees and certifi... Read more
Patient Concerns about Mental Health Medication Side Effects Remain a Barrier to Getting Help for Those Diagnosed with Depression and Anxiety Lisa Roberts has raised a family, reached an impressively high level in her career, and was an anchor for her mother and other family members. When, within ... Read more
Patient Common Antidepressant Side Effects Taking an antidepressant can be an effective way to help treat a mental health condition like depression or anxiety. However, these medications can also cre... Read more
Patient MTHFR Mutations: Clinical Implications and Management Strategies MTHFR mutations—changes in the methylenetetrahydrofolate reductase (MTHFR) gene—have gained increased attention in the medical community due to their potent... Read more