MTHFR: Going Beyond C677T and A1298C

The MTHFR C677T and A1298C variants get a lot of press – from Facebook groups to whole websites that talk about them.

But there is more to the MTHFR story than just those two variants!

This article gives you the bigger picture, including MTHFR variants with positive or protective outcomes.

Going beyond MTHFR 677 and 1298

MTHFR is a key gene in regulating the body’s folate metabolism. The folate cycle interacts with the methylation cycle, supplying the body’s need for methyl groups.

I’m assuming that you already know a little about the methylation cycle and the MTHFR C677 and A1298C variants.

If you don’t know your status on those two, check out this page: MTHFR: How to check your data for C677T and A1298C, and read through the background information on the methylation cycle.

In a nutshell, the methylation cycle is a cellular cycle responsible for creating methyl groups (CH3). These methyl groups are used by the body in tons of different reactions as well as to modify gene expression. Thus, alterations to the availability of methyl groups can have a wide range of impacts.

When reading about MTHFR, most articles only cover the C677T and A1298C variants. But those two variants do not give the whole picture for the MTHFR gene. Other variants also impact the way the MTHFR enzyme functions – both positively and negatively.

Also, keep in mind that diet is important here. Many of the impacts of MTHFR variants are mitigated through a diet rich in folate or choline.[ref]


MTHFR Genotype Report:

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Variants that decrease MTHFR enzyme function:

In addition to the MTHFR C677T and A1298C variants, the G1793A variant also significantly decreases enzyme function.

Check your genetic data for rs2274976 G1793A or R594Q (23andMe v4, v5; AncestryDNA) known as :

  • T/T: associated with cleft lip, OR 3.46[ref] neural tube defect[ref], higher homocysteine, and folate deficiency[ref] increased risk of schizophrenia in children[ref][ref] cognitive issues possible for seniors with this genotype in conjunction with low vitamin B12[ref]
  • C/T: somewhat increased risk of schizophrenia, cognitive issues possible for seniors with this genotype in conjunction with low vitamin B12[ref]
  • C/C: typical

Members: Your genotype for rs2274976 is .

 

Variants that are associated with positive outcomes:

Check your genetic data for rs9651118 (23andMe v4; AncestryDNA):

  • T/T: most common genotype
  • C/T: decreased risk of liver cancer[ref] slower cognitive decline in elderly[ref] lower homocysteine, type 2 diabetes (compared to T/T)[ref][ref]
  • C/C: decreased risk of lung cancer[ref] lower homocysteine, type 2 diabetes (compared to T/T)[ref][ref]

Members: Your genotype for rs9651118 is .

Check your genetic data for rs13306560 (23andMe v4; AncestryDNA):

  • T/T: avg 5.2 mmHg lower diastolic blood pressure[ref], Protective against Parkinson’s[ref]
  • C/T: avg 2.6 mmHg lower diastolic blood pressure
  • C/C: typical

Members: Your genotype for rs13306560 is .

Check your genetic data for rs17367504 (23andMe v4, v5; AncestryDNA):

  • G/G: protective against hypertension, preeclampsia[ref]
  • A/G: protective against hypertension, preeclampsia
  • A/A: typical

Members: Your genotype for rs17367504 is .

Check your genetic data for rs4846049 (23andMe v4; AncestryDNA):

  • G/G: decreased risk of migraines[ref], lower relative risk of cervical cancer[ref]
  • G/T: typical
  • T/T: typical, most common genotype

Members: Your genotype for rs4846049 is .


Lifehacks:

If you have variants that decrease your methylation cycle function, you may want to bring your levels up to the normal range.

Increase your folate intake:

Foods that are high in folate include:[ref]

  • Beef liver
  • Lentils, black-eyed peas
  • Spinach
  • Broccoli
  • Avocados

Read more: Folate-rich foods and recipe ideas

If you don’t eat enough folate-rich foods regularly, methylfolate supplements are also available. The RDA for folate is 400 mcg/day for adults (600 mcg/day for pregnancy). Tracking your folate intake using an app, such as Cronometer, for a week or two should give you a good idea of how much folate you regularly eat.

Choline-rich foods:

Choline can help your body bypass a lack of folate in the methylation cycle.[ref][ref]

Good sources of choline include egg yolks, beef liver, and wheat germ. A metabolite of choline, betaine, is actually what works via the methylation cycle; therefore, food sources of betaine (beets, quinoa, and spinach) are also helpful here. Supplemental betaine (also called TMG) is also available.

Read more: Choline-rich foods and recipes

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Related Articles and Genes:

Top 10 Genes to Check in Your Genetic Raw Data
It can be overwhelming when you are getting started with learning how your genes affect your health. What is actually important? Does it really matter if something increases your risk of an obscure disease by 10%?

Choline – An Essential Nutrient
Choline is an essential nutrient that a lot of us don’t get enough of. In fact, the majority of the US population doesn’t get enough choline on a daily basis. Insufficient choline can impact mental sharpness, heart health, fatty liver disease, and more.

Should you take folic acid if you have MTHFR variants?
There is a lot of buzz online about MTHFR variants and the need to avoid folic acid. I’ve seen recommendations ranging from avoiding all processed foods fortified with folic acid — to recommendations that people with MTHFR variants need to take extra folic acid.

Hypertension Risk Factor: CYP11B2 Variant
Hypertension risk can be modifiable in terms of diet and exercise however, genetics can play a part in risk. Learn more about how the CYP11B2 variant can increase the risk of hypertension.

 

References:

Abhinand, P. A., et al. “Insights on the Structural Perturbations in Human MTHFR Ala222Val Mutant by Protein Modeling and Molecular Dynamics.” Journal of Biomolecular Structure & Dynamics, vol. 34, no. 4, 2016, pp. 892–905. PubMed, https://doi.org/10.1080/07391102.2015.1057866.

Aneji, Chiamaka N., et al. “Deep Sequencing Study of the MTHFR Gene to Identify Variants Associated with Myelomeningocele.” Birth Defects Research. Part A, Clinical and Molecular Teratology, vol. 94, no. 2, Feb. 2012, pp. 84–90. PubMed, https://doi.org/10.1002/bdra.22884.

Beydoun, May A., et al. “One-Carbon Metabolism Gene Polymorphisms Are Associated with Cognitive Trajectory among African-American Adults.” Neurobiology of Aging, vol. 84, Dec. 2019, p. 238.e5-238.e18. PubMed, https://doi.org/10.1016/j.neurobiolaging.2019.05.013.

Cai, Can, et al. “Association of MTHFR, SLC19A1 Genetic Polymorphism, Serum Folate, Vitamin B12 and Hcy Status with Cognitive Functions in Chinese Adults.” Nutrients, vol. 8, no. 10, Oct. 2016, p. E665. PubMed, https://doi.org/10.3390/nu8100665.

de Aquino, Sibele Nascimento, et al. “MTHFR Rs2274976 Polymorphism Is a Risk Marker for Nonsyndromic Cleft Lip with or without Cleft Palate in the Brazilian Population.” Birth Defects Research. Part A, Clinical and Molecular Teratology, vol. 100, no. 1, Jan. 2014, pp. 30–35. PubMed, https://doi.org/10.1002/bdra.23199.

Ganz, Ariel B., et al. “Genetic Impairments in Folate Enzymes Increase Dependence on Dietary Choline for Phosphatidylcholine Production at the Expense of Betaine Synthesis.” The FASEB Journal, vol. 30, no. 10, Oct. 2016, pp. 3321–33. PubMed Central, https://doi.org/10.1096/fj.201500138RR.

García, Silvia, et al. “Analysis of the Rs13306560 Functional Variant in the Promoter Region of the MTHFR Gene in Sporadic Parkinson´s Disease.” Neuro Endocrinology Letters, vol. 38, no. 4, Aug. 2017, pp. 257–60.

García-Minguillán, Carlos J., et al. “Riboflavin Status Modifies the Effects of Methylenetetrahydrofolate Reductase (MTHFR) and Methionine Synthase Reductase (MTRR) Polymorphisms on Homocysteine.” Genes & Nutrition, vol. 9, no. 6, Nov. 2014, p. 435. PubMed, https://doi.org/10.1007/s12263-014-0435-1.

Hustad, Steinar, et al. Riboflavin and Methylenetetrahydrofolate Reductase. Landes Bioscience, 2013. www.ncbi.nlm.nih.gov, https://www.ncbi.nlm.nih.gov/books/NBK6145/.

Jadavji, Nafisa M., et al. “B-Vitamin and Choline Supplementation Increases Neuroplasticity and Recovery after Stroke.” Neurobiology of Disease, vol. 103, July 2017, pp. 89–100. PubMed, https://doi.org/10.1016/j.nbd.2017.04.001.

Office of Dietary Supplements – Folate. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/. Accessed 28 Dec. 2021.

Salehi, Mohaddeseh, et al. “The Rs4846049 Polymorphism in the 3’UTR Region of the MTHFR Gene Increases the Migraine Susceptibility in an Iranian Population.” Journal of Pain Research, vol. 11, 2018, pp. 145–49. PubMed, https://doi.org/10.2147/JPR.S152930.

Swartz, Michael D., et al. “Investigating Multiple Candidate Genes and Nutrients in the Folate Metabolism Pathway to Detect Genetic and Nutritional Risk Factors for Lung Cancer.” PLoS ONE, vol. 8, no. 1, Jan. 2013, p. e53475. PubMed Central, https://doi.org/10.1371/journal.pone.0053475.

Tanwar, Himani, et al. “A Computational Approach to Identify the Biophysical and Structural Aspects of Methylenetetrahydrofolate Reductase (MTHFR) Mutations (A222V, E429A, and R594Q) Leading to Schizophrenia.” Advances in Protein Chemistry and Structural Biology, vol. 108, 2017, pp. 105–25. PubMed, https://doi.org/10.1016/bs.apcsb.2017.01.007.

Thomsen, Liv Cecilie V., et al. “The Antihypertensive MTHFR Gene Polymorphism Rs17367504-G Is a Possible Novel Protective Locus for Preeclampsia.” Journal of Hypertension, vol. 35, no. 1, Jan. 2017, pp. 132–39. PubMed, https://doi.org/10.1097/HJH.0000000000001131.

Tomaszewski, Maciej, et al. “GENETIC ARCHITECTURE OF AMBULATORY BLOOD PRESSURE IN THE GENERAL POPULATION – INSIGHTS FROM CARDIOVASCULAR GENE-CENTRIC ARRAY.” Hypertension, vol. 56, no. 6, Dec. 2010, pp. 1069–76. PubMed Central, https://doi.org/10.1161/HYPERTENSIONAHA.110.155721.

Troesch, Barbara, et al. “Potential Links between Impaired One-Carbon Metabolism Due to Polymorphisms, Inadequate B-Vitamin Status, and the Development of Alzheimer’s Disease.” Nutrients, vol. 8, no. 12, Dec. 2016, p. 803. PubMed Central, https://doi.org/10.3390/nu8120803.

Wan, Lin, et al. “Age Matters: An Atypical Association Between Polymorphism of MTHFR and Clinical Phenotypes in Children with Schizophrenia.” Journal of Molecular Neuroscience: MN, vol. 69, no. 3, Nov. 2019, pp. 485–93. PubMed, https://doi.org/10.1007/s12031-019-01382-0.

Wang, Han, et al. “Association of Tagging SNPs in the MTHFR Gene with Risk of Type 2 Diabetes Mellitus and Serum Homocysteine Levels in a Chinese Population.” Disease Markers, vol. 2014, 2014, p. 725731. PubMed Central, https://doi.org/10.1155/2014/725731.

—. “Association of Tagging SNPs in the MTHFR Gene with Risk of Type 2 Diabetes Mellitus and Serum Homocysteine Levels in a Chinese Population.” Disease Markers, vol. 2014, 2014, p. 725731. PubMed Central, https://doi.org/10.1155/2014/725731.

Zhang, Donghong, et al. “Elevated Homocysteine Level and Folate Deficiency Associated with Increased Overall Risk of Carcinogenesis: Meta-Analysis of 83 Case-Control Studies Involving 35,758 Individuals.” PloS One, vol. 10, no. 5, 2015, p. e0123423. PubMed, https://doi.org/10.1371/journal.pone.0123423.

Zhang, Sheng, et al. “Association between Methylenetetrahydrofolate Reductase Tagging Polymorphisms and Susceptibility of Hepatocellular Carcinoma: A Case-Control Study.” Bioscience Reports, vol. 39, no. 11, Nov. 2019, p. BSR20192517. PubMed, https://doi.org/10.1042/BSR20192517.

Zhou, Bao-Sheng, et al. “Tagging SNPs in the MTHFR Gene and Risk of Ischemic Stroke in a Chinese Population.” International Journal of Molecular Sciences, vol. 15, no. 5, May 2014, pp. 8931–40. PubMed, https://doi.org/10.3390/ijms15058931.

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Zhou, Xinyue, et al. “The SNP Rs4846048 of MTHFR Enhances the Cervical Cancer Risk through Association with MiR-522: A Preliminary Report.” Molecular Genetics & Genomic Medicine, vol. 8, no. 1, Jan. 2020, p. e1055. PubMed, https://doi.org/10.1002/mgg3.1055.


About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.