Genetic testing can give us tremendous insight into our own health and, more importantly, our optimal diet and lifestyle choices given our genetic predisposition. I’ve long held that the Paleo diet is far from a one-size-fits-all approach and try to steer away from Paleo dogma in all of my writing. In this series, I’ll be covering specific genes that can tell us a lot about disease risk and how we can modify our implementation of Paleo to mitigate that risk. You may be able to request genetic testing through your doctor (my functional medicine doctor ran genetic screening on me as part of my first evaluation) or you can order a genetic test to do at home. I recommend 23andMe which you can purchase here.
MTHFR might sound like something you’d say after stubbing your toe, but it’s a word we all need to know when it comes to genetics! The MTHFR gene codes an enzyme called methylenetetrahydrofolate reductase, which plays a key role in the methylation cycle. The methylation cycle is the process by which the body recycles methyl groups, which are used to control the activity of a huge variety of proteins through the post-translational modification methylation. Some extremely important hormones (such as cortisol and melatonin) and some extremely important neurotransmitters (such as epinephrine and serotonin) are controlled through methylation. The methylation pathway is also critical for producing glutathione, one of the most essential cellular antioxidants in the body. Along with protecting against free radical damage, glutathione plays a role in the detoxification of certain carcinogens, heavy metals, and harmful chemicals (such as BPA). Methylation is also a process used by the liver in phase 2 detoxification (see What The Heck Does Our Liver Do Anyway? Detoxification Explained). More specifically, methylenetetrahydrofolate reductase helps convert 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (also called 5-MTHF), which is the body’s main biologically active form of folate. 5-MTHF, in turn, is used in a number of critical processes, including DNA reproduction and breaking down homocysteine into methionine. So, the MTHFR gene (and the enzyme it codes) can impact some of the most important activities in our body!
When our methylation cycle is humming along smoothly, we don’t have much to worry about (at least as far as methylation is concerned). But, several important MTHFR mutations exist that reduce our ability to convert folate into the form we need at the cellular level. When this happens, we can experience a higher risk of numerous problems occurring downstream from MTHFR enzyme insufficiency.
All of us carry two copies of the MTHFR gene (one inherited from each parent), and one or both of these copies can be in the form of polymorphisms that reduce MTHFR enzyme activity (depending on the mutation, enzyme activity can drop by 30-70%!). In particular, the gene variants C677T and A1298C can significantly reduce our ability to process folate. This is especially true for people homozygous for C677T (carrying two copies) or compound heterozygous for C677T and A1298C (one copy of each; A1298C on its own doesn’t appear to cause significant problems). An estimated 60-80% of the population carries at least one MTHFR mutation, with up to 25% being C677T homozygous (the riskiest combination). In other words, this mutation—including the most severe forms of it—is far from rare!
Across numerous large studies and meta-analyses, MTHFR polymorphisms (especially C677T, and especially when homozygous) have been associated with a higher risk of migraine, recurrent pregnancy loss, having children with neural tube defects, depression (particularly among Asian populations), lung cancer, breast cancer (for C677T, but generally not A1298C), aortic aneurism (especially among younger non-smokers), Parkinson’s disease (for C677T only), gastric cancer and liver cancer (for C677T only; A1298C appears protective for both of these cancers!), PCOS (particularly among Caucasians), thyroid cancer, bladder cancer, ovarian cancer (primarily among Asians), peripheral arterial disease, Alzheimer’s disease, hypertension (for C677T only, and particularly among Caucasians and East Asians), and schizophrenia (across multiple populations, including Asians, Africans, and Caucasians). MTHFR polymorphisms are also strongly linked to autoimmune disease, specifically type 1 diabetes, Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis, vitiligo, and multiple sclerosis.
MTHFR mutations are also linked to homocysteinemia (elevated levels of homocysteine in the blood), due to a reduced capacity for the enzyme to help convert homocysteine into SAMe. Although homocysteinemia has historically been believed to contribute to cardiovascular problems like heart disease and venous thrombosis (blood clots), more recent research suggests that elevated homocysteine associated with MTHFR defects doesn’t necessarily raise the risk of these conditions—at least not consistently. Some studies have found a mild risk-raising effect of the C677T polymorphism among Africans, but a protective effect among North Americans and the elderly.
Although MTHFR defects have sometimes been implicated in autism spectrum disorders as well, for the most part, the association only shows up in countries that don’t have a system of food fortification in place (and therefore where folate deficiency is more common).
Whew! That’s a lot that can go wrong from a defect in a single gene. So, what should we do if we carry a MTHFR mutation in order to combat these elevated risks?
Unfortunately, there’s not much we can do to improve MTHFR enzyme activity and establish normal folate conversion. That part is pretty much genetically hardwired. Instead, our best bet is to support our methylation pathways with a nutrient-dense diet that’s particularly rich in a few key nutrients! These include:
In addition, because people with MTHFR mutations have trouble converting folate and folic acid into their biologically active form, an already activated form of folate (L-5-MTHF) is sometimes recommended as a supplement—especially for pregnant women (who can experience pregnancy complications from inadequate folate) or C677T homozygotes (who may have trouble converting enough 5-MTHF from the folate in their diet, even with plenty of leafy greens and liver). If you fall into either of these categories, work with a doctor who can help determine your dosage. Taking too much 5-MTHF can cause over-methylation, which comes with its own set of problems!
Apart from nutrition, certain drugs (including contraceptive pills and Methyltrexate) can reduce folate levels, and other drugs (including proton pump inhibitors, or PPIs) can block the absorption of vitamin B12. People with MTHFR mutations who use these drugs may have even higher needs for methylation-supporting nutrients.
So, who should get tested for MTHFR polymorphisms? Considering the wide-ranging impact these mutations can have on our health (as well as the health of our offspring), knowing whether we carry them can be extremely valuable for virtually anyone. However, many doctors are resistant to ordering MTHFR tests for people who are asymptomatic. Women with a history of miscarriages and people with already-established high homocysteine levels are more likely to have the support of their doctor in ordering a test. For the rest of us, genetic testing companies like 23andMe can help us determine our MTHFR status (and the website GeneticGenie.org can directly interpret our 23andMe data to tell us our methylation profile!).
Although MTHFR might seem as bad as the other word it reminds us of, we can avoid facing a lifetime of increased risk by making smart food, lifestyle, and (if necessary) supplement choices!
Don’t forget to save your FREE spot in the upcoming Interpreting Your Genetics Summit! I’m excited to be speaking along some incredible thought leaders! Join us as we share the best practices for using genetic information to alter your lifestyle, guide treatment and create better health! This is the perfect time to order your 23andMe and then join me this August 21-28th for this incredible online event!
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