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).

Understanding the MTHFR Gene

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.How did it get so complicated?

I was thrown headlong into this debate when asked to write a chapter for the fourth 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 patient communities until taking on this challenge. I can boil down my conclusion into six words: “Treat the patient, not their genes.”

The Challenges of Testing for Overmethylation

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 overmethylation?). 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.

Genetic Testing Considerations

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.). 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 a patient’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


Tom Guilliams Faculty member

The Bottom Line

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.


Headshot Thomas G. Guilliams, PhD

Thomas G. Guilliams, PhD (Tom) earned his doctorate in molecular immunology from the Medical College of Wisconsin in Milwaukee. For the past two decades, he has spent his time investigating the mechanisms and actions of lifestyle and nutrient-based therapies, and is an expert in the therapeutic uses of dietary supplements. Tom serves as an adjunct assistant professor at the University of Wisconsin School of Pharmacy and was the VP of Science for Ortho Molecular Products for 24 years (he now serves them as a consultant). Since 2014 he has been writing a series of teaching manuals (Road Maps) that outline and evaluate the evidence for the principles and protocols that are fundamental to the functional and integrative medical community.  He is the founder and director of the Point Institute, an independent research and publishing organization that facilitates the distribution of his many publications. A frequent guest-speaker, Dr. Guilliams provides training to a variety of health care disciplines in the use of lifestyle and natural medicines. He lives in the woods outside of Stevens Point, Wisconsin with his wife and children.


  1. Bueno 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.
  2. Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014 Jan 1;533(1):11-20.
  3. Hiraoka M, Kagawa Y. Genetic polymorphisms and folate status. Congenit Anom (Kyoto). 2017 Jun 9. doi: 10.1111/cga.12232. [Epub ahead of print]
  4. Colson 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.