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Methylation—What Is It and Why Should You Care?


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Revolution Health Radio podcast, Chris Kresser

Methylation is a vital metabolic process that happens in every cell and every organ of our body.  Life would simply not exist without it.  It takes place more than a billion times per second in the body. That should give you some idea of how important methylation is.  Anything that’s happening a billion times per second is probably pretty crucial to our survival and well-being.  It happens when one molecule passes a methyl group, which is a carbon atom linked to three hydrogens, to another molecule, so it’s a pretty basic biochemical process.  These reactions that occur when one molecule passes a methyl group to another make things like creatine, carnitine, CoQ10, phosphatidylcholine, melatonin, and tons of other really important substances in the body.

In this episode, we cover:

0:57  What Chris had for breakfast
6:36  What is methylation?
14:12  The developmental origins of health and disease hypothesis
20:52  What affects how the body methylates
31:58  Where to get testing and treatment

Steve Wright:  Hey, everyone.  Welcome to another episode of the Revolution Health Radio Show.  This show is brought to you by ChrisKresser.com.  I’m your host, Steve Wright from SCD Lifestyle, and with me is integrative medical practitioner and New York Times bestseller, healthy skeptic Chris Kresser.  Chris, how’s your morning?

Chris Kresser:  It’s great.  How are you doing?

Steve Wright:  Pretty great.  I’ve already had, like, seven vials of blood drawn off me today, so it’s been a good start.

Chris Kresser:  Oh, wow.  Getting some testing done.  Nice.

Steve Wright:  Yeah, it’s my annual checkup I do.

Chris Kresser:  Good.  Hope it goes well.

What Chris Ate for Breakfast

Steve Wright:  Thank you.  So what did you have for breakfast this morning?

Chris Kresser:  Yeah, Steve, we haven’t done that for a while.  I think the natives are probably getting restless!

Steve Wright:  They are.  They want to know.

Chris Kresser:  It’s good timing because I didn’t have my typical breakfast.  We actually tried something new this morning.  We had flourless plantain waffles.

Steve Wright:  Ooo, that sounds delicious.

Chris Kresser:  Yeah, we learned about this recipe from a friend, Jessica, who learned about it from The Paleo Mom, which I think is Sarah Ballantyne, right?

Steve Wright:  Yes, it is.

Chris Kresser:  I love plantains.  Anyone who has listened to the show for a while knows I eat them pretty regularly.  I often have them in the morning.  I will usually just slice them and fry them in a little bit of expeller-pressed coconut oil because that’s easy and quick, but there are so many great uses for green plantains.  They’re such a great starch carbohydrate source for people on a paleo type of diet, and I just had the idea this morning to write a post about green plantains and all the different ways you can use them that was inspired by my breakfast.  So anyway, you can make batter for either pancakes or waffles super easily by just taking green plantains, putting them in the blender with eggs and coconut oil, some baking powder, soda, a little bit of maybe nutmeg or vanilla extract if you want, blend it up, pour it in the waffle iron or on the griddle, and that’s it.  You’ve got great flourless pancakes.  We’re not even talking about nut flour or coconut flour here.  It’s just pure plantain as the base, and that’s 100% paleo.  It’s not a flour-based product at all, so I think it’s probably even a little bit better than the nut flour and coconut flour products, which are pretty easy to overeat because of how they’re broken down that way and processed in flour, and it’s even less processed, and they were delicious.  I thought they were great, so I’m excited about that, and I’ll get that post up soon with some recipes for how to use plantains in a number of different ways.

Steve Wright:  Yeah, that sounds delicious.  Now, did you use a waffle maker?

Chris Kresser:  We did have an old waffle iron lying around.  We occasionally, really occasionally would make, like, almond-coconut flour mix type of waffles, but we had to dig that thing out.  It was really quick to make them, and they were really good.  Sylvie loved them.  She was thrilled to be eating waffles, and that’s the only kind of waffles she gets, so she loved it!  We cut up some strawberries and put a little bit of coconut whipped cream on there.  It was great.

Steve Wright:  I knew there had to be some fat in there somewhere.

Chris Kresser:  Oh, yeah, and butter, of course.  But there’s coconut oil in the waffles, too, so there’s fat built into the mix.  Delicious.  Highly recommend it.

Steve Wright:  Awesome.  Well, before we get to this week’s question, I just want to let everybody know if you haven’t been over to ChrisKresser.com, Chris has been spending a lot of time and energy and resources over there to redo the site and make it very easy to navigate and find all the work that he’s been doing.  And you’ll notice on the front page there that he has allowed everybody to get access to his 9 Steps to Perfect Health eBook.  This eBook was taken off the market for a while, and he has re-released it.  It’s a 63-page eBook, and obviously it has the 9 steps that Chris has been taking about for perfect health for a long time.  We’ve done a number of podcasts on these steps, but if you want the greater detail, including probably some references and hyperlinks and things like that, I’d really encourage you to go over to ChrisKresser.com, put your name and email in there, and go ahead and get that eBook and start reading it today.

Chris Kresser:  All right, so we have another great question.  Thank you, everybody, for sending in your questions.  They’re coming in fast and furiously now, which is great.  Lots of really good questions, and it’s so great to have a show that’s listener driven because that way I know that we’re giving you the information that you want.  We’ve gotten a lot of good feedback on the new format.  People seem to really enjoy the shorter, single-topic episodes.  They like hearing from other people who are listening to the show, hearing their questions played back.  It seems to be working well, so keep it up.  Keep sending up your questions.  So let’s have a listen.  This one is from Leslie.

Question from Leslie:  Hi, my name is Leslie.  I’m homozygous for MTHFR defect on the C677T gene, and so is my son.  I have autoimmune issues, and my son is autistic, and my husband we know is heterozygous.  And I just wanted to know your opinion on treating these mutations, what you typically recommend for your patients, those that have the double gene defect and those with the single.  Thank you.

Chris Kresser:  OK, great question, and there’s so much discussion about MTHFR and methylation out there these days.  I’m sure this is going to apply to a lot of people or interest a lot of people.  Let’s kind of take a step back from Leslie’s question and cover some basics about methylation, what it is, why you should care about it, and then we’ll dive into the specifics because it’s a topic that can get pretty complex pretty quickly.

Steve Wright:  Yeah, I’m excited to cover the basics again because I swear they don’t stick in my head.

Chris Kresser:  Yeah.

Steve Wright:  Can you, just for my pleasure, Chris, and hopefully probably a few listeners, make sure to cover heterozygous and homozygous one more time because I always forget that, too?

Chris Kresser:  Sure, no problem.

What Is Methylation?

Methylation is a vital metabolic process that happens in every cell and every organ of our body.  Life would simply not exist without it.  It takes place more than a billion times per second in the body.

Steve Wright:  Wow.

Chris Kresser:  That should give you some idea of how important methylation is.  Anything that’s happening a billion times per second is probably pretty crucial to our survival and well-being.  It happens when one molecule passes a methyl group, which is a carbon atom linked to three hydrogens, to another molecule, so it’s a pretty basic biochemical process.  These reactions that occur when one molecule passes a methyl group to another make things like creatine, carnitine, CoQ10, phosphatidylcholine, melatonin, and tons of other really important substances in the body.  Methylation controls sulfur metabolism, which balances the need for methyl groups, glutathione to control oxidative stress, and other sulfur metabolites like cysteine, taurine, and sulfate.  Methylation influences the production of ATP, which is the fundamental energy unit of the cell.  If you remember back to your high school biology course, you probably remember ATP.  If the cell can’t produce ATP, then there’s going to be inadequate energy in the body, nothing will work well, and you get a breakdown or an impairment of your mitochondrial function.

So this is something that can affect pretty much every tissue and organ system in the body, as you can see, because it’s working on the most fundamental processes within the body.  Methylation, in particular, though, seems to affect certain systems more than others.  One of the main systems is the brain and the production of neurotransmitters.  With methylation defects, you see autism spectrum disorders, ADHD, all kinds of cognitive and behavioral issues, depression, anxiety, etc.  Those are really typical manifestations.

It affects detoxification.  As I mentioned, methylation is required to produce glutathione, which is one of the major molecules in a detoxification cycle, but if you don’t methylate properly, you won’t be able to detoxify properly, so what this can lead to is a higher susceptibility to heavy metal toxicity and toxicity from any source like pesticides, other environmental toxins and pollutants, mold toxicity, toxicity from lipopolysaccharide or any other bacterial or pathogen-based toxin – so just in a general, an increased susceptibility to toxic overload because the body is not able to detoxify properly.

Methylation also influences histamine breakdown in the gut.  A lot of people recently have become more aware of histamine intolerance and mast cell activation syndrome.  We’ve talked about those on the show, I’ve written about that a little bit, but what a lot of people don’t know is that one of the potential underlying causes of histamine intolerance is poor methylation.

So methylation can affect just about anything, but it seems, like I said, preferentially to affect the brain, cognitive issues, the gut, and the detoxification system perhaps a little bit more than most other things.  Those are the problems we tend to see clinically more than anything else with people with methylation issues.

A little more about the basics of methylation that’s important to understand is one of the most crucial functions of methylation is that it regulates gene expression, and by that I mean methylation controls the turning on and turning off, which is otherwise known as activating and silencing, genes, gene expression.  A methyl group binds to a gene, and then it changes the way that a gene expresses itself.  This is known as DNA methylation, and it’s one of the mechanisms that cells use to control gene expression.

Steve Wright:  Now, is this epigenetics?

Chris Kresser:  This is epigenetics.  When you go back to the age of Darwin and then the discovery of DNA, scientists basically thought that biological inheritance was something permanent.  It was set in stone.  You inherit the genes your parents gave you, and then that’s what you pass on to your children, and there’s no change.  It’s hardcoded, the DNA.  It doesn’t change.  But over the last couple of decades, we’ve learned that genetic inheritance is a lot more complicated than that.  We know now that environmental factors like diet and stress and sleep and toxins lead to molecular changes that are not encoded in DNA, so they’re not actually changing the hardware of the system, if you want to use a computer analogy.  But those changes are still passed down to children and even grandchildren, so even though they’re not affecting the hardware, they are affecting the software, and the software, in a sense, is passed down to the children in a way that can affect their hardware or can affect the health of future generations.

So you have this really complex interaction between the genes themselves and then all kinds of environmental factors that regulate and activate or suppress the expression of those genes, and that whole sum total of influences, things that we’re exposed to, that our parents were exposed to even before they conceived or at the time of conception, which is amazing to think about, and then what we were exposed to in utero, and then what we’re exposed to through our whole life is now known as the exposome.  It’s the sum total of all of these epigenetic influences that can affect our gene expression.  That’s a really new term.  A lot of this stuff is really new in terms of the understanding of science.  As you said, Steve, this is known as epigenetics, and I want to give you some examples of how this works because I’m sure a lot of people are kind of scratching their heads right now; it can be a little bit abstract.

A couple examples from the animal kingdom, and there are many, but one would be depending on the time of year that they’re born, baby voles are either born with a thick coat of hair or a thin coat.  If they’re born at a time of year where the weather is warmer, there will be an epigenetic change that changes the expression of the genes that code for hair production, and they’ll be literally born with a different coat depending on what time of year they’re born.  In fact, more accurately, the gene for the thick coat is always there for these voles, but it’s just either turned on or off depending on the level of light that the mother senses in her environment, so once again that’s a way that the environment interacts with gene expression.

There’s a freshwater flea called the Daphnia that produces offspring with a larger helmet and spines, which are protective mechanisms for the flea, if it’s born into an environment that’s crowded with predators.  I’m not sure exactly how that works, but I imagine there is some sort of stress signals that the mother experiences which then affect gene expression and leads to the infant flea being born with more protective mechanisms.

The Developmental Origins of Health and Disease Hypothesis

This works in humans, too.  Studies have shown – there’s a new one that just came out very recently – that a mother’s and even a father’s diet at the time of conception, so not even just her diet during pregnancy, but the father’s diet prior to conception and at the time of conception and the mother’s diet prior to and at the time of conception affect not only their children’s health, but their grandchildren’s health.  This article was actually called You are What Your Grandmother Ate, which is really a profound concept to take in.  I mean, it really kind of puts everything in a whole new perspective.  Our responsibility for our bodies and taking care of ourselves and eating a good diet is not just about our own health or even our children’s health if we have children, but our grandchildren’s health.  That’s probably pretty heavy for some people to contemplate, but we’re learning more and more about this, and it’s true even for fathers, which is really new.  We didn’t really understand the role that the father’s diet played in the health of the offspring.  It seems like that would be mostly, if not completely, related to the mother’s diet, but we now know that the father’s diet can cause epigenetic changes that affect sperm quality, and then the changes in sperm will affect the health of the offspring and even the offspring’s offspring.

Steve Wright:  I’m just really excited that my grandma basically subsists on coffee and dark chocolate.  I’m pretty excited right now.

Chris Kresser:  Yeah, an antioxidant-rich diet, right?

Steve Wright:  Exactly!

Chris Kresser:  We have another study that came out recently.  We’ve known for some time that kids who are born to mothers who have had C-section have a higher risk for developing obesity and metabolic disease and other conditions, and one of the main reasons for that is because of the effects of C-section on the gut microbiome, but scientists have actually identified another reason, which is that C-section births cause changes in gene expression that then contribute to these potentially lifelong changes in health.  Now, that doesn’t mean if you’ve had a C-section your child is doomed.  The good news about epigenetics is that a lot of these factors which we considered to be unchangeable before are, in fact, modifiable by changing the environmental influences.  The bad news is that environmental factors like C-section and poor diet and everything can alter gene expression in a negative way, but the good news is that a good healthy diet and then fixing the gut microbiome and all the things that we talk about can have positive changes on gene expression in the future.

Steve Wright:  Yeah, it takes that whole ‘I got dealt a bad hand’ and now you realize you get to go fish as much as you want.

Chris Kresser:  That’s right!

Steve Wright:  You can throw the cards back in and go pull some others.

Chris Kresser:  Yeah.  I mean, certainly there are factors that are more modifiable than others, so it’s not like we have complete control over this.  There are genetic factors that we can’t change that influence our health, but I think we’re learning more and more that we have a lot more control and influence than we thought we did.

The last example in humans of how methylation can affect gene expression and how that translates into lifelong health is something called the Developmental Origins of Health and Disease hypothesis.  This is a theory that came out of research by a scientist named Barker, I think, in the ’80s in the UK, and he noticed that rates of heart disease were increasing in the UK, and everybody thought, oh, this is a disease of affluence; the rates must be increasing because people are eating more rich and fatty food, etc.  But what he noticed is the highest rates of heart disease were actually in the lowest-income communities where they definitely were not affluent.  He was puzzled by this, and he did some research to figure it out and found that the people with the highest risk of early heart attack before the age of 65 later in life were people who were born at the lowest birth weight, which indicates poorest nutritional status of the mothers.  So what he pieced together was that if the nutritional status during pregnancy is poor, that triggers epigenetic mechanisms in the developing baby to hoard calories when it’s born because essentially the baby senses that it’s being born into an environment of scarcity because it’s not getting the nutrients that it needs to thrive.  In the body’s wisdom, at a time when that was actually true, when there weren’t many nutrients, it would have been a survival advantage for that baby to be born with a system that would aggressively store whatever nutrition was available.  Then these babies are born and they have a much higher risk of obesity and metabolic disease and, thus, cardiovascular disease later in life.

Really fascinating stuff, and methylation is one of the main mechanisms that controls this turning on and off of genes.  So that’s the background.

Steve Wright:  Just to wrap this area up, the pre-training for the answer here, in case anybody was as curious as I was, a vole is kind of like a mouse.  It kind of looks like a little mouse.  I was really confused for a long time here.

Chris Kresser:  Right, I should have said that.  A little rodent-like creature, yeah.

Steve Wright:  Yes.

Chris Kresser:  Thanks, Steve.  This is why you’re here, one of many reasons, actually, so my runaway brain doesn’t get out of control.

All right, so let’s get back to Leslie’s question, and I still am tracking your question, Steve, about heterozygous and homozygous.  We’re going to talk about it in this next section here.  Leslie notes that she’s homozygous for MTHFR and has family members that are heterozygous, and there’s autism and autoimmune disease, which as I described earlier, those are fairly typical manifestations of methylation defects because of the effects of methylation on brain and immune system, detoxification, etc.  She wonders how you should treat those mutations and what you should do.

What Affects How the Body Methylates

Well, again, we need to kind of take a step back here and look at why methylation goes wrong in the first place and how you figure out what the cause of your methylation problems is or what the causes are and then what to do about it.  There are many things that affect how the body methylates, but they can really be broken down into two categories.  One is genetics and the other is environmental factors.  The environmental factors would be gut health, diet, exposure to toxins, stress, all of the typical environmental factors that we talk about on this show that affect our health.  But then there’s genetics.  There are several enzymes in the methylation cycle, and if you want to geek out a little bit, you can go to Google and type in ‘methylation cycle,’ and you’ll see lots of crazy charts with lines going everywhere and connecting.  It’s a pretty complex cycle.

Steve Wright:  Makes my brain hurt.

Chris Kresser:  Yeah!  You can find some simplified versions that are a little bit easier to understand, but it’s an extremely complex metabolic cycle, and it involves the action of several enzymes that are coordinated.  Mutations in certain genes that code for those enzymes can lead to decreased activity of those enzymes and, thus, decreased activity of methylation in general.  The most important enzymes in that cycle are MTHFR – that’s probably the one that’s best known; it stands for methylenetetrahydrofolate reductase – and then CBS, COMT, VDR, MTR, and MTRR are other genes that are involved in the methylation cycle.

Now, we inherit these genes from both parents.  You get genes from one parent and genes from the other parent, right?  If you have two copies of a mutated gene, you’re considered to be homozygous.  That means both of the copies of the MTHFR gene that you have that you inherited from parents are mutated.  If you’re heterozygous for a mutation, that means you have a single normal, non-mutated copy of the gene and then you have another copy that’s mutated.

Generally with genetic conditions, homozygous mutations are more serious because you have, of course, two mutated copies of the gene and whatever that gene does, whatever enzymes that that gene codes for are not going to be produced as effectively when there are homozygous mutations.  Depending on the gene and the mutation, a homozygous mutation can be quite serious in some cases, like with familial hypercholesterolemia, a genetic mutation that leads to very high levels of cholesterol.  If someone is homozygous, which means they have two copies of the mutated gene, they will often die in their 20s if not before that because they are completely unable to produce LDL receptors for their cells, which means they’re unable to clear LDL out of their circulation at all, and that leads to a very high LDL particle number, which leads to atherosclerosis, which leads to heart attack and death.  People who are heterozygous for that mutation tend to have very high total cholesterol levels, like over 300, 350, 400, even into the 500s.

That’s a very serious homozygous mutation that can be fatal, and even the heterozygous mutation can be quite serious, but with methylation, even if you have the homozygous mutation, you have a decreased activity of that enzyme of about 60%, so you have only 40% of the normal enzyme activity.  In many people, that will produce symptoms, but not in everybody, so that’s an interesting thing to understand about these methylation effects.  And then with the heterozygous mutations, depending on what genes are affected and what the specific nature of the mutation is, you’ll get varying levels of decreased enzyme activity.  In some cases, a heterozygous mutation isn’t really associated with much of a decrease in enzyme activity at all.  In other cases, it’s associated with more of a decrease.

Then, of course, those environmental factors are not isolated from the genetic factors, right?  You have someone with a genetic mutation for MTHFR and maybe some other mutations in some of the other genes, like CBS and COMT, and that person has been exposed to mercury, they’ve had SIBO and leaky gut and many other gut infections, they are extremely stressed out, they’re sleep deprived, they’re not exercising, they’re eating a poor diet, and then you compare someone with the exact same genetic picture to somebody else who has a healthy gut biome and a great diet and is exercising and managing stress and sleeping well.  Logic and clinical experience both would dictate that those people will have probably very different actual methylation capacity because of the influence of environmental factors on genetics.

Steve Wright:  Do we also have to take into account here, Chris, that just because you’re homo or hetero on one of these different genes, it might not be actually be switched on or off, the methylation of it?

Chris Kresser:  If you’re homozygous or heterozygous, it’s a good question, but it indicates that that mutation of the gene is there and there’s very likely to be reduced activity.  It’s a little bit different than the epigenetics of whether the gene is switched on or off, but it’s actual mutation in the gene itself.

Steve Wright:  OK.

Chris Kresser:  This is a change in the hardcoding.  It’s not an epigenetic change.

So if you have these genetic mutations, what it means is you’re more likely to have methylation problems, and that typically would manifest with low levels of folate, of adenosylcobalamin or methylcobalamin, which are the active forms of B12; S-adenosylmethionine, or SAM; or other metabolites in the methylation cycle.  It also typically leads to low levels of reduced glutathione, which is the beneficial form; possibly high levels of oxidized glutathione, which is potentially harmful; high levels of S-adenosylhomocysteine.  You get a buildup of homocysteine in the blood, which is an inflammatory molecule.  There are all these potential markers for poor methylation, and then this in turn leads to increased susceptibility to toxins, impaired detox capacity in part because of the glutathione, increased susceptibility to infections because of the immune dysregulation that causes histamine intolerance, depression, anxiety, chronic fatigue, infertility, and miscarriage.  Methylation defects are a very common cause of infertility and miscarriage and a whole array of other problems.

But as I mentioned before, the really key thing to understand is there isn’t a one-to-one relationship between mutations in the methylation cycle and actual methylation problems and symptoms.  Methylation mutations are not like mutations in genes that cause things like sickle cell anemia or cystic fibrosis.  If you have a mutation in that gene, it’s virtually guaranteed that you’re going to develop those conditions, and that’s not how it works with methylation.  There’s a lot more of a range in terms of how people are affected.  The best way to think about it is as a predisposing factor that could potentially lead you to having problems with methylation depending on all the environmental factors that we mentioned and probably some factors that we don’t even fully understand yet, including the interaction of other genetic mutations that you might have.

This is where this stuff starts to just get really, really complex, yeah, and it’s one of the reasons why I’m excited about genetic testing and the potential for all of these tests to help us clinically to treat patients as clinicians and also to get treated as patients, but I think we need to be cautious about extrapolating too much from these things.  I think we’re really kind of in the infancy of understanding how these mutations affect health in general and how other mutations in the methylation cycle will affect the basic mutations in MTHFR, which is the most common enzyme that people often check.  There’s a lot of work out there, like the work of Dr. Amy Yasko, that speculates on the influence of all of these other mutations in genes like COMT and CBS and VDR.  And when you start getting into that, as anyone who’s listening to this show if they’ve looked into that at all, you see that it’s a real hornet’s nest.  It’s like, OK, if you have this mutation, this kind of cancels out the effect of this other mutation, but then you have to look at this other mutation gene to see what effect that will have, and people who go down that road often end up taking about 52 different supplements based on all this mutations, and the evidence base for how those mutations affect one another is very thin.  We have evidence definitely on MTHFR and how those mutations affect human health, but beyond that, there’s very little information in the peer-reviewed scientific literature about CBS mutations or COMT or any of that sort of stuff.  That doesn’t mean that some of the clinicians out there who are on the frontier aren’t right, and it doesn’t mean that they’re not doing valuable work, but it does mean that if we’re going to stick with the scientific method, we want to see these things studied and reproduced, especially when they lead to patients spending a lot of money and making big decisions about their health.  That’s just a kind of sidebar.

Steve Wright:  Yeah.  This is where we’re entering into the art of medicine.

Chris Kresser:  Absolutely.

Steve Wright:  And there are people that can really benefit from those doctors, and I know of several.

Chris Kresser:  Yeah.

Steve Wright:  But I think it’s a great point that let’s differentiate these and make sure people know what they’re in for.

Chris Kresser:  Yeah.  Lack of proof is not proof against, as I’ve often said, and we need more research here.  It’s just something to know that some of this stuff falls into the realm of clinical experience, which is totally valuable in many cases, but we need more research.

Where to Get Testing and Treatment

Let’s just talk briefly about testing and treatment.  The genetic testing, one of the best ways to get tested is 23andMe.com.  A lot of people know that the FDA shut them down from doing health interpretation of their data, but the good news is you can still get the raw data.  It’s 99 bucks, I think.

Steve Wright:  Yeah.

Chris Kresser:  You go to 23andMe.com, you order it, and when you get the results back, you can go to a few different sites to get it interpreted, get the methylation genetics interpreted.  One of them is GeneticGenie.org.  You go there, you click on Methylation Analysis, and it hooks up to your 23andMe data and it spits back a report.  A much more comprehensive report is available at MTHFRSupport.com, and this can give you information that will probably just totally confuse you unless you have any training in this area, but it’s something that you can then take to your functional medicine practitioner for interpretation.

Steve Wright:  And you’re liable to learn really fascinating things like what I learned, which is that I have a genetic defect for being prone to sneezing fits.  I always thought that it was just that my inflammation was really high, but I’m just prone to sneeze.

Chris Kresser:  Yeah, and you can learn if you’re homozygous for MTHFR.  That’s useful information to have because it’s likely you’ll have a tendency toward folate deficiency and low glutathione and other things that we talked about before.  It’s really good to know that.

But as I mentioned, genetics do not always predict functional methylation capacity, which means how you are actually methylating.  I really believe that we need to be testing both of those things as clinicians because one doesn’t, as I said, predict the other necessarily.  There are different ways to test functional methylation capacity.  Doctor’s Data has a methylation panel blood test.  Health Diagnostics and Research Institute has a Methylation Pathways Panel that’s good and I tend to use in my practice.  Genova has a Complete Hormones profile that, among other things, looks at the ability to convert proliferative estrogen metabolites into less proliferative metabolites, and those conversions are methylation dependent.  So if you see poor conversion happening there, that’s a methylation issue.  The urine organics acids profile from Genova has some methylation markers, active folate and B12 deficiency.  And then a urine amino acids profile can be helpful to look at taurine levels and levels of other metabolites in the methylation cycle.  Those tests can be helpful.  You can talk to your physician or functional medicine clinician about that.

If you have decreased methylation on a functional panel, then you would probably want to initiate a methylation protocol.  Those can really run the gamut.  Lots of people approach them differently.  One of the most popular and commonly used ones was developed by a great researcher and health advocate named Rich Van Konynenburg who sadly passed away last year, I think.  But if you search for ‘Rich Van Konynenburg methylation protocol,’ you’ll find it.  I do recommend working with someone on this because there’s a risk of over-methylation if you become too aggressive with the methylation supplements.  That can cause its own problems.  When you start methylating, you’re going to be up-regulating your detox capacity, so that can cause a lot of die-off type of symptoms as your body starts to clear toxins that have been stored for a while or latent infections, things like that.  It is something you can do on your own in the sense that a lot of the supplements that are used, like B12 and folate, are pretty safe, but it’s better if you can find some supervision because it can be kind of difficult to work through sometimes.

This was a little bit longer of an episode than normal.  It’s a pretty complex topic and hard to cover in a 20- or 25-minute format, and I know we’re only scratching the surface, but I hope this was helpful, Leslie and everyone else that’s listening, and we’ll come back to you next week.

Steve Wright:  Yeah, thanks, Chris.  Obviously this is a new area of research and new area of clinical experience, and so definitely the takeaway, I think, here for Leslie is to get the extra next-level testing for all of her entire family to figure out where those genetic defects are actually causing issues or if they are causing issues because we don’t know that data yet, and then from there, a protocol could be created based on that test results.

Chris Kresser:  Yeah.  I mean, it’s likely they are in her case because she mentioned autism spectrum and autoimmune disease in the family and those are typically correlated with methylation, but they’re also multifactorial, many different causes, many different possibilities.  But it’s definitely good for you to get that functional methylation testing, Leslie, for you and your family.  Steve, thanks for being here, and we’ll see everybody next week.

Steve Wright:  Yeah, thanks, Chris.  And the light bulb just went off in my head from sixth grade science or maybe seventh grade that a homogeneous solution is one that is completely dispersed and a heterogeneous one has the solids, and so if we think back to our genetic question of homozygous and heterozygous, then you can learn whether they’re both copies or one of the other copies, so thank you.

Chris Kresser:  Yeah, if you talk about a homogeneous culture, you’re talking about one that’s very similar; everything’s kind of the same.  Heterogeneous is more diverse and varied, so that’s another way to think about it.

Steve Wright:  Perfect.  Well, thanks, Chris.

Chris Kresser:  All right.  Take care, everybody.

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Join the conversation

  1. you mention the importance of knowing one’s “functional methylation capacity” aka testing it, since MTHFR compound hetero or whatever are merely predispositions and may not be at play even if we have many symptoms. i’d like to do that. what are 2 tests to look at or order up re best bang for buck? that folks with MTHFr can afford to test out of pocket annually?

  2. Can anyone answer these question? Why have CFS/Fybromyalgia (I assume most of these cases probably involve methylation issues) cases skyrocketed since the 90s? And why is it so prevalent in the US ad much less in third world countries?

  3. I am wondering about MTHFR deficiency and homocysteine levels. I know that glycine breaks down homocysteine. I eat a lot of gelatin, connective tissue, etc. My homocysteine level is low (a good low), and I am heterozygous for both MTHFR snps (and working with a functional medicine doctor about it). Does having good homocysteine levels autoatically mean I have proper methylation, or is it possible for a person to lower their homocysteine levels with glycine but not be methylating properly?

    Thank you,

  4. I really enjoyed this article, but does anyone know exactly which studies are referenced when he says, “Studies have shown – there’s a new one that just came out very recently – that a mother’s and even a father’s diet at the time of conception, so not even just her diet during pregnancy, but the father’s diet prior to conception and at the time of conception and the mother’s diet prior to and at the time of conception affect not only their children’s health, but their grandchildren’s health.”
    I’d be really interested to read the papers published from these studies. Also I just make it a habit of always reading the actual raw source before totally believing what someone says about studies being done, no matter how much I’d love to just trust it. 🙂

    • I second what Joshua said and would love some sources listed for these studies, they sound great, I just always like to go to the original source!

  5. I just went to the 23andMe website and they are no longer doing the testing. Any suggestions as to where else I could go to get tested for Methylation?

  6. This topic is very interesting. I just my 3 month checkup with my MD. She is not like your usual mainstream doctors, she spent 1 hour discussing my health issues. My doctor told me she is 95% sure have I have MHTFR mutation. I ask about being tested and she replied that it would not change the course of treatment, when I pushed to be tested, her reply was that with way health care is going in the USA, DNA test can reveal info that you really don’t want on your medical record and that one of the MHTFR mutations would indicate you will develop Alzheimer’s. It can be like opening Pandora’s Box. What is your opinion on DNA testing concerning this issue for me and also for others?

    • Hi Charlotte,

      Great question! Genetic testing does not tell you how much methyl is present so looking at individual SNP’s is like going into a tug of war battle because there is no way of knowing which genes will express themselves. DNA is not functional, only your unique biochemistry is. Functional testing is what tells us what’s really going on inside your body at the present time.

      Gene expression is mostly due to epigenetic markers that are heavily influenced by diet and environmental factors, nutrient deficiencies, and toxins.

      Your doctor is correct that getting the MTHFR test will not alter your course of treatment.

      • Actually, I would want to know. The 677T and 1298C mutations each have different baggage that go along with them. But they are NOT the only troublesome methylation mutations. NOT knowing which other ones you have could lead to a bad treatment plan.

        Testing that one MTHFR gene in a doctor’s office cost us $400. The 23andme test, which will give you info on dozens of methylation mutations, has been far more valuable for individualizing treatment for each member of our family, and your health insurance won’t know.

        MTHFR doesn’t cause Alzheimer’s, or for that matter, anything else. It’s that defective gene, activated by bad things in your diet and environment, in coordination with your other methylation genes, that can produce a whole host of problems, from brain diseases, to leaky gut, to heart disease and cancer.

        And, for most of these genes, around 30% of the population shares the bad version, so having one does not make any of us so special to be singled out.

        What it DOES mean, is that likely you dont deal with toxins too well and are much more likely to have one or more diseases that go with that, so eating a clean diet and avoiding toxins is a smart strategy, along with a wisely designed nutritional supplement plan.

        Do the 23andme test and run the results through MTHFRsuppport or Geneticgenie then take that to your doctor… You’ll quickly find out if you have a knowledgeable one or not – it’s far more than MTHFR.

  7. Dr. Kresser, what is your recommendation for B vitamins? I take B vitamins because I had mercury problems and my testing from Metametrix said that I needed lots of different B vitamins (that was 4 years ago when I was sick). I used to take a few different B vitamins, but a different dr. put me on pure encapsulations B Complex Plus multi. And she suggested I stop taking B12 shots because me homocysteine was too low. It came up to 5.6 from 3.8 after discontinuing the B12 shots. I am doing well in lots of ways, but I do have reactions to foods and I think histamine is a main sensitivity. Would you recommend continuing on my B vitamins? I know I needed them 4 years ago, but I wonder about now. I have been working on my liver because of hormonal symptoms, food sensitivities and elevated liver enzymes.

      • Thank god he’s not a ‘traditional’ doctor.

        All they do is dish out drugs to TEMPORARILY SUPPRESS SYMPTOMS, while Chris has studied and researched ways to bring the body back into balance so that it can truly heal and one can recover.

        • Not the point! ANY doctor, Chris is not one. It’s misinformation, and allowing that information to go uncorrected is unconscionable on its own. He is a researcher and “practitioner”. If he were a “traditional” doctor, how would that make you feel? Better about doctors I suppose? Meantime, it is erroneous to call him a doctor. and potentially a liability. But more than that, people are deluded to think it. NOW, this doesn’t diminish Chris’ work, so that’s not the point.

          • Lara,

            No need to YELL, although your time might be better spent learning how to spell and use punctuation properly so that people could begin to take you seriously.

            Your post, from what I can make of it, is hypocritical at the very least. First you rant and scream that he’s not a doctor, then say that this ‘doesn’t diminish Chris’ work’.

            And I answered your question(s) in my original reply.

          • Jeez, take a chill pill. He’s not obligated to reply to every incorrect thing that’s said about him.

          • Excuse me here, but making a point that Chris is not a doctor is null. The curriculum in medical school is archaic in that it covers very little information based on the mapping of the human genone. Our current medical paradigm is based on disease and the pharmacological model of symptom based drug intervention. Until medical schools catch up with current technology and there is a shift in this paradigm it will be the MD’s that go above and beyond what they were taught and other health care interventionists, scientists and the like that take a role in fixing our broken system and truly begin to heal the wounded and sick.

  8. Thank you so much. I had the 23andme test and didn’t show any methylation gene issues. Nice to know it’s more complex.

  9. I get so confused with all of this information. I have a 16 year old son who seems to break all of these rules. I have taken him to so many doctors and spent so much money, but I end up trying to figure it out myself. He has tested high in histamine, normal zinc,very low copper, low ceruloplasmin, low folic acid,borderline high in kryptopyroles and so he really doesn’t fit into the typical undermethyliation, overmethylation, pyroluria as far as testing goes. He seems to fit the picture for undermethylation as far as symptoms, such as high anxiety, allergies, argumentative nature, etc. He is very sensitive to high histamine food as they tend to give him nasty migraines. I started giving him a multivitamin that had 400 mcg of folic acid about a week and a half ago because his regular pediatrician said he is malnourished, but he started having bad allergy attacks. I stopped giving it too him a couple of days ago and the sneezing fits seem to be stopping now. I’m not sure if it would have been the folic acid in the multivitamin that could have caused this. I’m not sure, since he tested low in serum folic acid if I should try supplimenting him with L. methylfolate to see how he responds to this. I just ordered the 23andme testing, so I guess I will wait to see if anything shows up there.

    • I would recommend checking out the book Nutrient Power by Dr. William Walsh.

      It sounds like your son is a classic undermethylator… and according to Dr. Walsh he should **avoid** any type of supplemental folate/folic acid.

      Typically, undermethylators need something like SAMe/methionine to help methylation, and react ver poorly to supplemental folates/folic acid. Also, consider supplementing with something like desiccated liver which contains very absorbable zinc and copper balance. Further, vitamin B6, serine, inositol, TMG, magnesium, fermented cod liver oil can all help the methylation process.

      • Please keep in mind that it is imperative you get tested before taking any nutrients. We don’t recommend supplementing without the proper functional tests.

        As the book’s title denotes, nutrients are powerful.

        Undermethylation symptoms are also similar to those of Pyrolle Disorder and Copper Overload, so again, please be careful when supplementing. Liver is high in copper and can be problematic. TMG and and inositol can also cause issues if the patient is not undermethylated.

    • Absolutely do not give him ANY folates or a multi vitamin…. He is a classic undermythelator and certain nutrients will increase histamine and decrease neurotransmitters leading to a worsening of his behaviors and mood.
      Our son was just like him – horrible rages; mood swings; depressed- anxious; seasonal allergies and insomnia. We took him to Mensah medical and its been 4 years on their individualized protocol – he has improved dramatically !
      He went from a boy with a Dx of bipolar; ADHD and anxiety to a normal child – only because of what the doctor at Mensah medical were able to do with him.
      The biggest blessing of my life! And before Mensah we had been to 5 doctors and he had been tossed from 2! Schools – by 2nd grade! His histamine was 148; low zinc; higher free copper and mild pyroluria; he follows his treatment plan of compounded nutrients… He is now 12 and a happy energetic well adjusted child!

    • You need to treat your son thru Mensah Medical. Folates will destabilize him as he is an undermethylated. Testing thru23&Me is not appropriate as it does not dictate HOW you treat.. my son was exactlu like yours – bipolar very oppositional and moody -horrible symptoms.. he has been a patient T of Mensah for past 7 years and his progress is amazing – really miraculous
      The leaders in this field are William Walsh Albert Mensah and just Bowman, MD

  10. These are some Gene reports you can use to get your results, get if you’ve run your 23andMe Ancestry Family Tree or Nat Geographic DNA Test:

    Standard Gene Report:

    AUTISM SPECTRUM DISORDER, ADHD, BIPOLAR DISORDER, MAJOR DEPRESSIVE DISORDER, AND SCHIZOPHRENIA: https://livewello.com/snps/library?action=preview&index=379628&for=johnadams

    THYROID RELATED GENES: https://livewello.com/snps/library?action=preview&index=427779&for=florence

    METHYLATION REPORT: https://livewello.com/snps/library?action=preview&index=899200&for=demo

    YASKO NUTRIGENOMICS GENES: https://livewello.com/snps/library?action=preview&index=55692&for=johnadams

    PARKINSON’S DISEASE: https://livewello.com/snps/library?action=preview&index=41870&for=demo

    E.G. CELIAC DISEASE: https://livewello.com/snps/library?action=preview&index=417820&for=demo

    LACTOSE INTOLERANCE: https://livewello.com/snps/library?action=preview&index=257796&for=florence

    All of the above and thousands more are free with a 1-time purchase of Livewello’s Gene Tool: https://livewello.com/snps

    • You can also upload your data at Genetic Genie, Know Your Genetics, or Methylation Support to get your detoxigenomic and methylation pathway charts. Free in most cases.

  11. Seriously, Steve, is there really a gene for predisposition to sneezing fits, or are you pulling our legs? I have always gotten sneezing fits for seemingly no reason at all (or something minor like suddenly getting bright light in my eyes). I have a very strong immune system, never get colds, get a touch of the flu maybe every 8-10 years, heal very quickly from cuts/scrapes/burns… but those infernal sneezing fits are maddening. I can sneeze for several minutes, and I get the histamine-type reaction (swelling membranes, drippiness, etc.). Thirty minutes later, it’s as if the fit had never happened. If the sneezing-fit gene is real, what nutrients help minimize it? Thanks!

    • Sneezing is just another method the body uses for purging stuff it doesn’t want, just like coughing, colds, vomiting, diarrhoea, rashes, boils, zits, fevers, sweats, etc.

      Everything has to be attributed to genes these days. Maybe there is a ‘sneezing gene’, but regardless, that is the route your body chooses to use as its predominant purging route. Other people may get rashes, or acne, or diarrhoea as their main route. It just depends on a body’s preferred way of detoxing itself.

  12. As usual, an informative and interesting episode. However, I would love to be able to print the transcript to find & review again later. Other sites offer a printer-friendly icon. Perhaps you would consider adding that to your website? 🙂