Gene Expression, Fish Oil, and MTHFR.

Fish oil, which we talked about last week as well, continues to be a big deal for people with the MTHFR mutation. Today, I want to discuss a couple of studies about gene expression, fish oil, and MTHFR, but first I want to make sure everybody understands the basics of gene expression.

When your body makes something out of your genes, it doesn’t just read the DNA and make a protein. There is more to it than that. The process, however, can be broken down into two big chunks – bear in mind that there is far more to it than this as well, but this will help you to understand the research we’re going to talk about..

  1. Transcription -Transcription is the process in which the DNA is opened like a zipper and mRNA is made from one side of the zip, and the resulting mRNA molecule is processed by the body.
  2. Translation – Translation occurs when the mRNA molecule we made above, is used to direct protein synthesis. This is how the MTHFR gene makes the MTHFR enzyme, which is the protein this gene codes for.

mRNA is genetic material just like DNA, but the difference is that while DNA might be the ultimate blueprint, it is also giant, double-stranded, and not easy to work with. RNA of all types, including messenger RNA, is single-stranded and generally transcribed from the master DNA. It is created in small segments and is the signal needed for your body to actually build proteins.

What this means is that mRNA is a good marker, in research, specifically this research about fish oil and MTHFR, for the action of the MTHFR gene and one of the only ways we can measure when the gene is acting.

Gene expression in the homocysteine cycle with Fish Oil and MTHFR

Last week we mentioned that levels of fish oil and homocysteine were linked – the higher the fish oil intake for the person studied, the lower homocysteine levels became. Let’s expand on that.

This study, published in Nutrition Journal, looks at the gene expression, meaning the mRNA levels for different enzymes along the homocysteine pathway. This includes MTHFR, but also other enzymes including MAT, CSE, SAHH, CBS, and MTR. See the diagram to place each enzyme within the pathways for recycling and converting homocysteine.

Human liver cells were treated with either decosahexaenoic acid, DHA, eicosapentaenoic acid, EPA, or alpha-linolenic acid, ALA for 48 hours. A control group with no treatment was also kept for 48 hours and then studied. After that time, mRNA levels were measured from each enzyme in question. It was found that:

  • MTHFR was upregulated by both DHA and ALA.
  • MAT was down regulated by all three treatment groups, but most in the DHA group.
  • CSE expression was increased in the DHA and EPA groups.
  • No significant changes were shown in SAHH, CBS, or MTR.
Omega-3 fatty acids like EPA, DHA, and ALA have an effect on the action of certain gene SNPS and the enzymes they code for.

This study is remarkable because it shows that the action of MTHFR can be influenced with something as simple as fish oil. The next study is even more remarkable.

Pregnancy, Fish Oil, and MTHFR

Methylation is one of the primary drivers of a person’s epigenetic state, and some of the most important methylation happens during gestation, so research involving this period is especially important. This particular study, published in Biomedical Research International, was conducted on rats.

Because previous research has shown that nutritional changes in the mother affect both poly-unsaturated fatty acid metabolism and global methylation in the placenta. This study theorized that the changes are due to some regulation of the maternal enzymes in the methylation cycle by dietary nutrients.

This study divided pregnant rats into six groups.

  • Normal folic acid and B12 (this is the control group)
  • Normal folic acid, B12 deficient
  • Normal folic acid, B12 deficient with omega-3 fatty acids
  • High folic acid, normal B12
  • High folic acid, B12 deficient
  • High folic acid, B12 deficient with omega-3 fatty acids

Placental mRNA levels were tested for MTHFR, MTR, MAT2a, CBS, PEMT, and GAPDH. Placental glutathione and phospholipid analysis were also performed.

In an effort to not bore your pants off, I’ll get to the relevant details about MTHFR.

As expected the mRNA expression of MTHFR was decreased in both B12 deficient groups relative to the normal B12 groups. Interestingly, omega-3 fatty acids were able to return the mRNA to a normal level in the normal folic acid, B12 deficient group but not the high folic acid, B12 deficient group.

This tracks with what we know about folic acid’s double-edged effect on the MTHFR enzyme. A small to normal amount is good (and far better than no folate intake) but too much inhibits the MTHFR enzyme

Placental glutathione levels followed much the same pattern. In the normal folic acid, B12 deficient group the glutathione levels were lower than normal (although not statistically significant). With excess folic acid however, glutathione levels with higher in those rats with normal B12 and significantly lower in the rats with B12 deficiency. Omega-3 fatty acids were able to correct the glutathione level in the normal folic acid, B12 deficient group but not in the excess folic acid group.

My theory about this is that glutathione manufacture is more difficult in the presence of imbalanced folate or B12, but that it increases in the most imbalanced group, which is excess folic acid and deficient B12, in an effort by the body to protect itself with glutathione buffers against increased oxidative stress.

Phospholipid levels tested higher in both B12 deficient groups compared to the control group. In both of those groups omega-3 supplementation reduced them.

This study is so remarkable because we’re looking at the time period when epigenetic is at it’s most potent and when the protective effects of omega-3 fatty acids could potentially alter the course of these pregnancies. While placental levels are being measured, these changes may have an impact for the developing fetus as well. This means that even in the presence of a somewhat unbalanced diet leading to unbalanced methylation, omega-3 fatty acids offer a regulating effect and may mitigate some of the worst of the consequences of the unbalanced diet.

Thus, the metabolisms of folic acid, vitamin B12, and DHA are interdependent on each other possibly through the one-carbon methyl cycle.

Khot V, Kale A, Joshi A, Chavan-Gautam P, Joshi S. Expression of genes encoding enzymes involved in the one carbon cycle in rat placenta is determined by maternal micronutrients (folic acid, vitamin B12) and omega-3 fatty acids. Biomed Res Int. 2014;2014:613078. doi:10.1155/2014/613078

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Fish Oil and MTHFR, What Is The Link?

We’ve all heard about fish oils and omega3 fatty acids for so many incredible reasons. They are strongly anti-inflammatory and perform almost as well as non-steroidal anti-inflammatory tests for pain relief, without side effects. 

They have been most strongly studied for heart disease and show an almost unbelievable array of benefits. Fish oils reduce the risk of sudden death from cardiac arrhythmias, reduce all-cause mortality in patients with known cardiac disease, and help to treat high cholesterol (hyperlipidemia) and high blood pressure (hypertension.) All of this, without significant side effects or drug interactions

Studies have also shown that countries with higher intake of omega-3 fatty acids have lower rates of depression. Fish oils have also shown beneficial effects in both research and clinical practice for diabetes, Alzheimer’s disease, stroke, and autoimmune disease. 

What about Fish Oil and MTHFR?

Most studies aren’t MTHFR-specific.  But, fish oil has benefits for so many of the long-term consequences of unbalanced methylation in MTHFR, that it makes sense that there would be some link.  What reserach has found is some kind of synnergy between fish oil and B vitamins, in which the combination works better than either therapy alone.

Omega-three fatty acids and B vitamins for cognitive decline

A randomized placebo-controlled  trial of people with mild cognitive impairment found that treatment with B vitamins lowered homocysteine and slowed the rate of cognitive decline. Researchers went back and re-analyzed the data from this study to see if baseline levels of omega-three fatty acids interacted wtih the results in any way. The study involved mental testing over the course of two years.They found that for all outcome measures, higher concentrations of DHA significantly enhanced the effects of B vitamins, while the levels of EPA had less of an impact.

Not only that, when omega-3 fatty acid levels are low, B vitamin treatment has no effect on cognitive decline, but when omega threes are in the high-normal range, B vitamin treatment becomes effective. There is some synnergy happening here that needs further investigation to fully understand, but since omega-three fatty acids are good for so many things and truly haven’t shown negative consequences it makes sense to add them in as a no-risk measure for seniors with cognitive decline.

Omega-three fatty acids and homocysteine

The methylation process itself seems to be involved in the metabolism and distribution of these polyunsaturated fats through your body, which means that MTHFR and omega-3s are intimately linked. Also, it has been theorized that omega-three fatty acids actually have expression control on enzymes within the methylation cycle, so effectively MTHFR controls omega-threes, which control MTHFR. There is not a big enough body of research yet to draw firm conclutions, but the evidence is pointing in this direction.  For MTHFR folks, the most important thing to understand is that using fish oils and B vitamins together produces a great reduction in homocysteine levels than using either one alone. 


This research suggests that omega-3 fatty acids (referred to here as PUFA or polyunsaturated fatty acids) actually stimulates the action of the MTHFR enzyme, which activates folate to generate SAMe, the methyl donor. PUFA also stimulates the MAT enzyme which converts methionine to SAM, the CCT enzyme which is involved in the conversion of choline to phosphatidylcholine, and the CGL enzyme which is involved in the conversion of Homocysteine to Glutathione. 

Inflammation, heart disease, cognitive decline, and high homocysteine are all problems that happen more frequently in folks who have MTHFR with unbalanced methylation, and since fish oils effectively address these problems, it almost seems like a gimme.

Next week, we’ll talk about a few bits of research being done regarding fish oil and gene expression for MTHFR folks. The research is new, but it’s starting to get good.

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Lowering Homocysteine with MTHFR

As with everything to do with MTHFR, balancing your methylation and boosting your B vitamins, especially B2, folate or 5-LMTHF, and B12, is the first step. Balance your methylation! There are some other things you can look into as well.

MTHFR Isn’t The Only Cause of High Homocysteine

Of course, our focus is MTHFR, but high homocysteine has other causes as well and the sad truth is, you can have fleas and ticks on the same dog. That is one of my favorite Texas expressions. What I mean by that is that just because you have MTHFR, doesn’t mean you don’t have to also watch out for other causes of high homocysteine. It’s important to manage those too. Other Causes of high homocystein (or hyperhomocysteinemia) include:

  • Poor diet
  • Poor lifestyle
  • Smoking
  • Diabetes
  • Rheumatoid Arthritis
  • Thyroid imbalance
  • Chronic inflammatory diseases
  • Celiac disease
  • Crohn’s disease
  • Long-term use of corticosteroids
  • Prescription medications
    • methotrexate (because it lowers folate)
    • metformin (long term use because it interferes with B12 absorption)
    • hydrochlorothyazide
    • Fibrate type cholesterol-lowering medications
    • Levodopa
    • Anti-epileptic drugs (long-term use)
    • Possibly nicotinic acid or niacin, but research is very conflicted.

If you have one of these underlying conditions or are taking a medication known to elevate homocysteine, then working on that condition or talking with your physician about the medication can be a great place to start. Outside of that, let’s talk about useful steps.

The MTHFR Plan to Lower Homocysteine To Optimal

  1. Balance your methylation – I’ve said it already, but the first step is always boosting your methylation cycle because this is where we tend to stall out with MTHFR. This means following the To Health With That! Plan. Eliminate folic acid, add a methylation-friendly B complex, then add 5-LMTHF, or folinic acid, or whatever workaround you are using if you don’t tolerate folate. If you aren’t familiar with the plan you can start to walk through it here.
  2. Limit your protein intake – The more protein (and consequently methionine) you take in, the more homocysteine your body makes. There’s a full article about the methionine and homocysteine link here.
  3. Quit smoking – As though you needed one more reason why smoking is bad for your health. But yes, smoking raises your homocysteine levels.
  4. Take a look at your alcohol intake – alcohol blocks folate absorption, and so increased drinking can raise your homocysteine levels. This is probably mitigated by extra folate intake, but possibly not.
  5. Balance your coffee intake – As much as it pains me, too much coffee has consequences and high homocysteine is one of them.
  6. Zinc – zinc is a cofactor in some of the enzymes involved in the recycling of homocysteine to methionine, and so zinc deficiency can increase homocysteine levels while zinc supplementation can help to improve beneficial conversion.
  7. NAC – NAC, or N-acetyl cysteine, has been shown to lower homocysteine levels as well as folate supplementation in studies.
  8. Fish oils – in a magical synergy, fish oils + B vitamins work better together than they do apart.
  9. Make sure there aren’t other underlying causes – If you’re doing everything right and your homocysteine still isn’t where you want it to be, it matters to talk to your doctor about other underlying causes. If you’re living the perfect lifestyle, but you still have a low thyroid, then fixing your thyroid is probably the only thing to bring your levels back to balance.

Don’t forget that every little step you take towards getting healthy, counts. They all add together to contribute to your state of health, today. So every little step you take in the right direction, matters. Don’t get discouraged if things don’t move right away, just keep trying.

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MTHFR and Homocysteine By The Numbers

These past few weeks we’ve gone over some general information about MTHFR and homocysteine, the link between methionine and homocysteine, and the new information about MTHFR, homocysteine, and Covid-19. What we haven’t talked about is Homocysteine testing and parameters – what is normal, what isn’t, and what is considered normal but maybe shouldn’t be.

Testing Homocysteine

Homocysteine tests are simple blood tests that can be ordered by your doctor. It must be performed fasting for accurate results. Any protein you eat before your test can skew the numbers because methionine in your food may cause a temporary rise in homocysteine. The best way to ensure a blood test is fasting is to schedule your blood test early in the day before you have eaten anything. 8 – 12 hours of fasting (like you would get overnight) is best for the most accurate results.

“Normal” Levels

The current medical standard in the U.S. is a normal range from 5 – 15 umol/L (that is micro mols/Litre). Anything above 15 micro mols/L is considered high, or hyperhomocysteinemia. There is a growing body of evidence that the normal level should be adjusted:

  • A study published in the New England Journal of Medicine shows that carotid artery thickening and stenosis risk begins to increase for men by 9.2 umol/L (although the risk for women seems to remain stable until 11.4 umol/L). Both of these are significantly lower than the 15 umol/L that is considered normal.
    • Risk increases at 9.2 umol/L
  • A meta-analysis published in the Journal of the American Medical Association shows that a 3 umol/L decrease in homocysteine leads to an 11% lower risk of ischemic heart disease and a 19% lower risk of stroke.
  • A strong linear relationship exists between homocysteine levels and death in patients with coronary disease. The lowest risk group has homocysteine below 9 umol/L and the risk increases from there both within what is considered the normal level and outside of it.
    • Homocysteine <9 umol/L = 3.4% risk of death
    • Homocysteine 9 umol/L – 14.9 umol/L = 8.6% risk of death
    • Homocysteine >15 umol/L = 24.7% risk of death.
    • Risk increases at 9 umol/L
  • The study we discussed last week dealing with homocysteine levels as a predictive marker for worse outcomes with Covid-19 also showed an increased risk for pathological lung changes on CT at 8 umpl/L
    • Risk increases at 10.58 umol/L

If The “Normal” Levels aren’t Ideal, What Is?

All of the risks for negative health outcomes seems to be lowest around the 6 – 8 umol/L mark, so we’re going to call that “Optimal.” This is an estimation based on the research that we talked about above. Joe Pizzorno (a legend in the natural wellness community), estimates the ideal range to be 5.0 to 7.0. Ben Lynch, the epigenetic expert, estimates ideal to be between 6 to 9 umol/L.

If Homocysteine Is So Bad, Why Aren’t We Aiming for Zero?

Too much homocysteine is bad for sure, and with MTHFR and homocysteine that is the direction we usually trend, but remember that homocysteine is absolutely essential. If your homocysteine is too low (hypohomocysteinemia), then there are also health consequences. Without homocysteine you can’t make glutathione, which is one of your main defenses against oxidative stress. Without glutathione, things would go sideways pretty quickly.

Homocysteine is also the precursor for something called alpha-ketobutyrate, which is a vital ingredient in the process that makes cellular energy. Very few studies are done about low homocysteine levels (I mean VERY few. I can count them on two hands). By far the most interesting one shows a link between low homocysteine and peripheral neuropathy. It states that fully 41% of people with low homocysteine have peripheral neuropathy, which is hugely significant.

In my opinion, this implies that the lack of glutathione and consequent difficulty with free radicals is leading to higher levels of inflammation and nerve damage. Ben Lynch put forward a similar theory on his website here, and Joe Pizzorno, here.

I wouldn’t be surprised to see a link between low homocysteine and chronic fatigue, as well, although the research has never been done.

The bottom line is that we need homocysteine, but too much of it becomes a big problem. Aim for 6 – 8ish micro mols/L. Next week we’ll talk about ways to lower your homocysteine levels if they’re too high.

Has your homocysteine ever tested too low? I”d love to hear your comments here, or in Genetic Rockstars, our amazing MTHFR community.

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Homocysteine, MTHFR, and Covid-19. What We Know Now.

Of course in a pandemic we all want to know how it might affect us specifically, with all of our genetic differences. That research takes time and money and usually comes after the big stuff (like how does this spread and why does it kill people.)

In good-ish news, Covid-19 has now officially been around long enough for some of the smaller, more specific areas of research to be done. This includes the very first steps on research into the interplay between homocysteine, MTHFR and covid 19.

This particular study came about because there have been big differences in COVID disease severity, in particular in the death rate, between different geographic areas as well as between the genders. The study I am talking about was published in November 2020 in a journal called Medical Hypotheses, which is not peer-reviewed research, but rather includes important theoretical papers, so I do want to emphasize that this information is theoretical and has not been formally researched yet.

Here is a Summary from The Article Entitled: Life-threatening course in coronavirus disease 2019 (COVID-19): Is there a link to methylenetetrahydrofolate reductase (MTHFR) polymorphism and hyperhomocysteinemia?

At the date of publication of this research, Covid-19 was associated with an 8.8% mortality rate in those above 60 years of age, and 0.46% for patients aged below 60 years old. Countries with the highest mortality rates are Italy, Spain, France, Iran, and the USA. A recent report from Italy showed that the vast majority of those infected who were critically ill were older men, 68% of whom had at least one comorbidity. The worldwide mortality rate is higher among men almost by a factor of two.

Mortality rate Male:Female = 1.7:1

In Italy, high rates of ICU admission, ICU mortality, and overall mortality have been seen and the deaths from COVID-19 are often associated with high neutrophils, high levels of pro-inflammatory cytokines, abnormal coagulation tests, and disseminated inter vascular coagulation.

The most common comorbidities among the most critically ill were:

  1. Hypertension
  2. Cardiovascular disease
  3. Hypercholesterolemia
  4. Diabetes

The article goes on to summarize the high points of MTHFR:

  • The MTHFR enzyme is the most important in the methionine pathway.
  • It regulates fundamental processes such as DNA repair, neurotransmitter function, and membrane transport.
  • The C677T mutation has been suggested to be protective against certain cancers including colon and acute lymphatic leukemia.
  • The mutation leads to a thermolabile variant of the MTHFR enzyme in which the dissociation rate of the cofactor Flavin Adenine Dinucleotide (FAD) (this is from B2) is increased, thus reducing the activity of the MTHFR enzyme by 50% or more.
  • In people with a medium skin tone, the function of the MTHFR enzyme is largely preserved as long as they have sufficient dietary folate intake.
  • With insufficient folate intake, the production of 5-LMTHF is reduced, which leads to the accumulation of the key metabolite, homocysteine, to toxic levels.
  • MTHFR is the most common genetic cause of hyperhomocysteinemia.
  • Low folate status resulted in significantly higher levels of homocysteine in men.
  • Research suggests that the C677T mutation is associated with a significantly increased risk of coronary artery disease only in homozygous men.

Other risk factors for the development of high homocysteine are:

  • chronic kidney failure
  • hypothyroidism
  • cancers of the breast, ovary, and pancreas
  • smoking
  • alcohol consumption
  • physical inactivity
  • advanced age
  • male gender

Acute High Homocysteine

In addition to the risks of high homocysteine that we have talked about before, an acute high homocysteine situation can be triggered, independent of folate status, when a systemic inflammatory process is triggered (like, for instance, by a virus). This process boosts inflammation and releases a tremendous amount of reactive oxygen species (free radicals), which can overwhelm your antioxidant defense systems. This is potentially an even greater issue in MTHFR folks because we have the potential for lower glutathione than average. This whole ugly cascade activates something called nuclear transcription factor (or NF-kB), which accelerates viral replication in SARS Co-V. The study also cites a case report in which glutathione supplementation led to a rapid symptom improvement in two cases of Covid-19.

Interestingly, COVID-19 patients’ plasma homocysteine levels show predictive value for the progression of pathological findings on chest CT. This means the higher the patient’s homocysteine is, the more likely they are to show damaging changes in their lung tissue on a chest CT scan. Also, these changes began to show at a lower homocysteine level than the one that is usually used as a medical reference. Negative changes began to show at 10.58 umol/L rather than the 15 umol/L that is normally recognized as a “high” value.

In Covid-19 patients, the higher the patient’s homocysteine is, the more likely they are to show damaging changes in their lung tissue on a chest CT scan.

– Karst M, Hollenhorst J, Achenbach J. Life-threatening course in coronavirus disease 2019 (COVID-19): Is there a link to methylenetetrahydrofolic acid reductase (MTHFR) polymorphism and hyperhomocysteinemia?. Med Hypotheses. 2020;144:110234. doi:10.1016/j.mehy.2020.110234
-(Paraphrased by Amy Neuzil at tohealthwiththat.com)

What Do We Do About High Homocysteine, MTHFR and Covid-19?

This study makes some suggestions.

  • Patients at high risk with Covid-19, such as the elderly with comorbidities, should also be screened for high homocysteine.
  • Those with 8 umol/L Homocysteine or above should implement a folate-rich whole foods diet (fruit, vegetables, whole grains, good protein sources.)
  • These individuals should also add 5-MTHF supplementation.
  • Folic acid should be avoided by these individuals as supplementation can have the opposite of the desired effect, especially in individuals with the MTHFR polymorphism. This is thought to be because unmetabolized folic acid accumulates, which inhibits MTHFR and also folic acid competes at binding sites with 5-MTHF.
  • B6, B12, and B2 should be added as well as they are cofactors for the MTHFR enzyme, or in the methionine pathway.
  • Supplements with demonstrated anti-viral properties can be added, including vitamins A, C, D, E, selenium, zinc, iron, and omega-3 fatty acids.
  • Strong antioxidants including vitamin C and glutathione have shown positive results for Covid-19 outcomes.

At the end of the day, it looks like taking care of yourself appropriately for MTHFR and following the positive steps to balance your methylation that we have been talking about, is actually the best defense for those of us with MTHFR against the worst of the outcomes with Covid-19. Taking positive steps to manage your MTHFR doesn’t mean that you won’t get Covid-19, but hopefully, it will help to reduce your risk of dying from Covid-19. Keep in mind that this study represents a well-researched theory, and it has yet to be proven in clinical trials.

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