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MTHFR: Treating Genes or Patients?

by Thomas G. Guilliams, PhD

In the discussion about nutrition, genetics and genomics, invariably the topic of methylation and genes related to methylation will find their way into the discussion. Chief among the genes mentioned in such conversations is MTHFR, the gene encoding one of the key enzymes responsible for “re-charging” the activated form of folate (5-MTHF), called methylenetetrahydrofolate reductase, along with a few of its well-known polymorphisms (e.g., C677T). If you have been following the MTHFR discussion over the past few years, you know how complex and confusing it has become. What first appeared to be a straightforward relationship between one gene and the need for higher or different intake of a nutrient (folate, folic acid, 5-MTHF) in subjects with specific polymorphisms has become a complex discussion of numerous related metabolites, nutrients, metabolic pathways and the genes and enzymes (and polymorphisms) that relate to the folate and methylation cycles. 1 How did it get so complicated?

I was thrown headlong into this debate when asked to write a chapter for the 4th Edition of the Integrative Medicine Textbook (Rakel, 2017). I took on the challenge of writing a chapter that was eventually entitled “MTHFR, Homocysteine and Nutrient Needs.” While I had written on this topic before, I hadn’t realized how much hype, confusion and misinformation existed on these topics in both the clinician and lay communities until taking on this challenge. I can boil down my conclusion into six words: “Treat the patient, not their genes.”

With the advent of (relatively) inexpensive genetic tests and bolstered by hundreds of epidemiological and mechanism studies from a quick search on PubMed, clinicians are now routinely testing patients for a variety of gene polymorphisms and confidently tweaking this or that B-vitamin based on those results. Specialized websites, often set up by well-intentioned clinicians, have popped up to guide both the clinician and the patient on MTHFR genotype-driven nutrient supplementation, with several supplement companies coming along for the ride.

But many clinicians are realizing that this approach is oversimplified and even therapeutically problematic (Is this really over-methylation?). Genotype, after all, is not the same as phenotype. Having a gene that creates a thermolabile enzyme (i.e., C677T) is clearly linked to a vulnerability for certain chronic disease conditions in population studies, but these vulnerabilities are nearly undetectable in people who are eating a healthy diet and have adequate levels of body folate stores.2 As has been mentioned over and over, gene expression is the root of overall phenotype, not merely gene sequence. Add to this the complexity of epigenetics, multiple copy number mutations, substrate availability, enzyme-turnover and so many more factors, and we see the simplistic genotype-to-phenotype dogma has more bark than bite.

This doesn’t mean that genotype doesn’t matter, or that genetic testing has no place in the clinical treatment of methylation disorders, elevated homocysteine or its associated risk disorders (e.g., heart disease, hypertension, Alzheimer’s disease, osteoporosis, etc.). It is clear that individuals with certain phenotypes have a higher incidence of elevated homocysteine within the general population and these risks can be reduced when given folate (both folic acid and 5-MTHF will work in all phenotypes, though small statistical improvements can be realized in some subjects using the latter compared to the former).3 Knowing someone’s genotype may certainly help the clinician look for risk where they may not have otherwise looked (this is a good thing); but it may also cause them to treat a person’s polymorphisms as if they are the risk itself (this is rarely a good thing). Genetic testing is also likely to help explain why certain therapies (in this case, folate or vitamin B12 supplementation) may require more aggressive dosing to accomplish an adequate clinical result (677TT homozygous individuals).4

In the end, genetic testing must be understood within the larger context of the patient’s lifestyle and environmental exposures. We often tell people that good lifestyle decisions can overcome high-risk genes and, sadly, poor lifestyle can undermine low-risk genes. Genetic testing is a powerful tool, but we must always remember that our genes are mostly the canvas upon which our life’s journey paints a picture. Learning how to incorporate genetic testing into lifestyle-based therapies can be a powerful adjunct to help focus on potential vulnerabilities and explain why some doses or therapies are more helpful than others. However, we should never imagine that treating a person based on their genotype is good medicine.

1Bueno O, Molloy AM, Fernandez-Ballart JD, et al. Common Polymorphisms That Affect Folate Transport or Metabolism Modify the Effect of the MTHFR 677C > T Polymorphism on Folate Status. J Nutr. 2016 Jan;146(1):1-8.
2Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014 Jan 1;533(1):11-20.
3Hiraoka M, Kagawa Y. Genetic polymorphisms and folate status. Congenit Anom (Kyoto). 2017 Jun 9. doi: 10.1111/cga.12232. [Epub ahead of print]
4Colson NJ, Naug HL, Nikbakht E, et al. The impact of MTHFR 677 C/T genotypes on folate status markers: a meta-analysis of folic acid intervention studies. Eura J Nutria. 2017 Feb;56(1):247-260.



About Thomas G. Guilliams, Ph.D

Dr. Guilliams earned his doctorate from the Medical College of Wisconsin (Milwaukee) where he studied molecular immunology in the Microbiology Department. Since 1996, he has spent his time studying the mechanisms and actions of natural-based therapies, and is an expert in the therapeutic uses of nutritional supplements. As the Vice President of Scientific Affairs for Ortho Molecular Products, he has developed a wide array of products and programs which allow clinicians to use nutritional supplements and lifestyle interventions as safe, evidence-based and effective tools for a variety of patients. Tom teaches at the University of Wisconsin-School of Pharmacy, where he holds an appointment as a Clinical Instructor; at the University of Minnesota School of Pharmacy and is a faculty member of the Fellowship in Anti-aging Regenerative and Functional Medicine. He lives outside of Stevens Point, Wisconsin with his wife and children.


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