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#06 – The latest science on MTHFR, dosing B vitamin supplements, APOE4 and more with Dr. Aaron Gardner

MTHFR is a gene that has generated a ton of interest in the health and wellness world, but many remain skeptical. A few years ago at SXSW in Austin I was practically laughed out of the room for asking a question about MTHFR to a panel of genetics experts. However, what are common mutations in these genes have been blamed on everything from autism to breast cancer to heart disease, but is there good science to back up these claims? We brought back Gene Food’s resident geneticist, Dr. Aaron Gardner to go over the latest research on MTHFR. We cover the lab tests that can help determine how well MTHFR and other methylation genes are functioning, ideal dosing for B vitamins, other genes that impact the methylation cycle and why an amino acid metabolite called homocysteine is a problem for many with MTHFR SNPs. The episode also touches on other genetic markers such as ApoE4 and whether a high fat diet is a good idea for carriers of this much-discussed genetic marker. At the end of the show, we get into omega-3 fatty acid metabolism and the histamine genes.

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This Episode Covers:

  • Basics of MTHFR [7:45];
  • MTHFR, lab tests and homocysteine [12:00];
  • B vitamin supplements, methylation and dosing [18:00];
  • CBS genes and other genes that impact methylation [27:46];
  • APOE4 and high fat diets [40:00];
  • FADS1, omega-3 fatty acid metabolism and DHA deficiency in Vegans [49:49];
  • Dangers of vegetable oil [1:00];

Discussion and Show Notes:

We’ve gotten into the basics of MTHFR in a number of blog posts:

And of course, we have the dedicated MTHFR page listed in our Guide to Nutrigenomics.

We touched on in the show, but providers like 23andme have taken a position that is “anti-MTHFR.”

One of the tips we give in the show to determine whether MTHFR and other methylation SNPs are “working” is to have homocysteine tested. This blog post also gives 7 genes linked to high homocysteine and how to lower that metric.

Boston Heart and Cleveland Heart Labs definitely test for homocysteine.

This is the blog post we referenced listing the various studies that looked at increased cancer risk when supplementing with B vitamins. This post also contains Aaron’s chart: B vitamins and cancer risk: what you need to know

Spectra Cell is a lab I mentioned that offers micro-nutrient testing.

MTRRone of the methylation genes Aaron mentions in the show.

CBS genes and sulfur metabolism. Here is a blog post I wrote on the CBS genes as well as our CBS gene page.

This is the Pure B vitamin product I discussed on the podcast with fairly conservative dosing of the various B vitamins. The good news is the product comes in capsule form and therefore it’s easy to adjust dosing.

As we get into APOE4, it may be helpful for some to take a look at our first podcast episode covering Ketogenic diets. Aaron references some promising studies in mice looking at ketogenic diets and APOE4. Those studies can be found here and here.

We also wrote this blog post titled Can a ketogenic diet prevent Alzheimer’s in APOE4 carriers?

As we go through the APOE4 discussion, I mention the “Retterstol study.” Here is a link. Retterstol is important because it shows wild differences in lipids when different people go on a high fat diet.

The discussion of Vegan diets and omega-3 fatty acid metabolism centers around FADS1 and this paper, which highlights the major differences in PUFA metabolism based on genetic variants and how minority populations are more likely to convert more omega-g fats into inflammatory bi-products like arachidonic acid.

Here is a link to the Nutrition Facts video recommending an algal oil supplement for Vegans.

I mentioned a study that looked at men with low EPA/DHA and how feeding them a diet high in plant sources of omega-3 actually caused DHA to go down. Here is the study.

These Algal oil brands are made with sunflower oil! what?

Here is a post I wrote titled Why I don’t eat vegetable oil.

And here is the NEJM study on Lp(a) which shows that Lp(a) binds preferentially to oxidized phospholipids.

I have been using the Cronometer app lately to track both macros and micronutrient intake.

AOC1 genes or as we called them, the “histamine genes.”

Zonulin and histamine – is there a link?

Transcript:

John: Welcome to “The GeneFood Podcast.” I’m your host, John O’Connor. Hey guys, before we get into today’s episode, I want to make you aware of our sister site, the GeneFood site is at mygenefood.com but we have a sister site that’s located at leafscore.com. That’s leafscore.com. Leafscore.com is a place where we are highlighting non-toxic and ecofriendly products and basically creating a whole rating system for giving people the tools they need to make sure they’re not using toxins and things like cosmetics or children’s toys. And so it’s just a massive site where we’re going to give you all the best products that are non-toxic and ecofriendly.

With that said, today’s episode is about the MTHFR gene. We get a ton of questions about MTHFR. Where does the science stand in MTHFR? Are there lab tests that you can turn to once you found out you have an MTHFR mutation to determine whether your MTHFR gene is working or not working? The different types of MTHFR polymorphisms, what MTHFR actually does, B vitamin supplement issues. And then we transition to some other genes that we’re getting a lot of questions about apoE4, nutritional interventions for apoE4. We touched on a previous podcast, but we continue to get a lot of questions, people want clarification. So we dive into apoE4.

And then we do some stuff with omega-3 fatty acid metabolism, some of the genetic markers there. And also we close on with the histamine gene. So there’s a lot of stuff here, especially if you’re looking for a tour of some of the best markers out there in nutrigenomics. So I think this is a nice place to start. And we have a good conversation, especially of MTHFR at the beginning. Enjoy the episode and thank you for listening.

John: Aaron, what’s up, man?

Aaron: Sorry, it took so long. I couldn’t get the Uber call through my desktop so for some reason, it kept kicking me out. So I’m just on my mobile.

John: That’s fine, man. How’s the UK? What’s happening in your neck of the woods?

Aaron: Not much, actually. The nice sun I was telling you about the last time you rang has disappeared, and it’s about to rain again. And bright ships just in the long grass again. So, you know, not much is happening really.

John: Just same old stuff. Yeah.

Aaron: Same old, same old.

John: Yeah, I hear that. We just sent out an email newsletter for the last episode of the podcast we did for the Joel Kahn episode. Dr. Kahn. I don’t know if you’ve checked that one out. And…

Aaron: I’ve not listened to the last one yet. No.

John: Yeah. I don’t think people were that happy with the title of the email that we that we chose, which is, “Do vegans have better sex?” I thought that was going to be pretty compelling. But I think actually, it seems to be making our email audience kind of angry. So if you listened to the last podcast…

Aaron: Do you get angry responses back?

John: Not angry responses back, but the click-through is not as high as it normally is. So if you’re one of the people who opened to that email and kind of rolled your eyes or whatever, we did try to give equal coverage to those issues. I actually have a lot of respect for Dr. Khan. I think he’s a…I mean, I said in the podcast intro, I know him both from his role as like a nutrition commentator, but also as somebody who’s just a very excellent doctor in his local communities. He’s very conscientious, very, very, very well respected.

But I think there’s just people are getting a little bit tired of kind of the whole, like, vegan propaganda thing, which I understand, I understand. We’ve said you and I in the past that we think a diet that skews a little more plant-based is healthy. But we’re going to touch on some of that here in a minute with this whole omega-3 fatty acid stuff. But true to the title of this podcast, we’re going to start off with another gene that we get a ton of questions on and that is MTHFR. So what’s your preliminary message to the audience on MTHFR and then I’m going to just fire off a bunch of stuff to ask you about?

Aaron: I mean, it’s probably the one that almost anyone who’s interested in nutrigenomics, even at a sort of surface level, it’s the one that you come across because it’s the most well studied, it’s probably the one with the most famous snip in it, that most people know about. And that’s because it’s one of the ones which has probably the most profound effects on health as and it can affect lots of different things. So because of that, there’s been lots of research done on it and lots of conflicting information is out there. So hopefully, today, we’re just going to drill down into some of the stuff that actually is really sound science.

John: The sound science, and also, the nature of science is to progress. So even if we’re not going to give a ton of attention or a tip of the hat to some of the more obscure theories in MTHFR, it’s not to say that in the future, there could be associations to all sorts of things with MTHFR, but it is a common gene. With these polymorphisms, there’s what’s called A1298C and C677T. How common are those “mutations,” Aaron?

Aaron: So for the C677T, the C allele is the sort of the standard one. And the T allele is the risk and the actual amount that people have varies. But I think it’s estimated now that about 30% of the population will carry a T allele for the C677T, which is the most common one. For the other one that you mentioned, the C risk allele, so that one, it’s a bit less common, but that particular polymorphism is also less involved in some of the health effects with MTHFR.

John: Yeah, we’re going to get into just some good stuff on C677T in a minute. But when I’ve heard of conversations about A1298C, I think that’s something that is theorized to touch on more cognitive issues, whereas the C677T is linked more to cardiovascular.

Aaron: Yeah, I mean, it’s even going beyond that. I think the A1298C polymorphism is being linked with other things outside of the C677T one. The strength of it has actually being decreasing over time as more and more studies are sort of performed.

John: Okay, good.

Aaron: It seems that more and more stuff is shifting towards the C677T for stuff that was previously ascribed to that 1298 has been shifted back over towards the 677T. So the actual importance of that one is still in flux. We still rate it quite highly because there is a lot of science out there. But I think it’s the 677T one is the really, really important one.

John: The 6770T is where we’re going to spend the meat of this conversation. If you are going to give…I have a one heterozygous copy of the 1298C. And based on all the work that I’ve done with you in terms of how you’re doing all these, the scoring system and the algorithm we have for our nutrition plans, I don’t tend to hyper focus on any one snip. I think it’s just part of a sort of a concert that we’re teasing out here. But if you were to give one takeaway, so there’s a lot of studies, what are some of the reliable issues that have been identified with the A1298C? And actually, sorry, we always do this. Prior to even getting into this, just for the people that are listening at home that haven’t heard of MTHFR and don’t know what it is, Aaron is going to get into a lot more of the mechanistic science issues here in a minute.

But top level, it’s a gene that helps your body break down and use B vitamins, especially folic acid. Folic acid is a cofactor and all these different metabolic processes in the body that linked to DNA repair. And basically, a healthy body needs to use these B vitamins. And for people that have MTHFR “mutations,” they have some degree of a diminished ability to use the full aid to do the things that it needs to do in terms of remethylating different amino acids and all that. So what do you have? Do you have something to add to that, Aaron? Just preliminarily because we always forget the foundational stuff.

Aaron: Yeah, I mean, you hit it right on the nail, on the head there. So MTHFR is an enzyme and the pathway that is responsible for converting sort of dietary intake of folate or folic acid habit, whichever form that we’re taking it in. It converts it into something that the body really needs, which is the sort of to provide methyl groups, which you say has used them all throughout the body for things like DNA repair and a whole host of other processes. So that then kind of ties in with why these polymorphisms are so important because if you have changes in their function, then you sort of can dramatically reduce that store of those methyl groups that the body needs. And that can then be associated with a lot of disorders.

So the one we’re going to talk about a lot is, you know, the cardiovascular risk that’s associated with homocysteine. But things like the actual decreased amount of methylation is also associated various types of arthritis. And just lots of things associate with that. So neurological disorders. The neurological disorders is interesting. I mean, neurological disorders are always quite difficult because they happen later on in life. And they’re often, you know, they’re multifactorial, but there is some evidence out there that they have associations with that. And again, it’s probably to do with the sort of inflammatory environment that these snips can generate in the body.

John: Yeah. So there’s a bunch of stuff that’s theorized, and we talked about, you know, the brain cancer and all these different things. I think it’s an important message to the audience they’re like, okay, so if you find through 23andMe, well, 23andMe is not reporting, I’m going to get to 23andMe’s take on this in a minute, which is they’re sort of like, you wanna say anti-MTHFR but their take is that MTHFR is really not proven. It doesn’t mean that you’re going to develop any of these diseases. And even if you have one or two mutations, you still have some enzyme activity, it’s just reduced.

Aaron: Yeah, it’s about a 30% to 70% reduction in enzyme activity that’s associated with a copy of the T allele, the risk allele. So obviously, if you have two copies, you’re at a higher risk. But you can see within that 30% to 70%, there’s a wide variation in activity. And then the other important bit is it’s a big cycle. It’s a big pathway with lots of enzymes. So although you may be deficient in one enzyme, you may be making up for it somewhere else in the pathway. So it’s always best not to just look at one thing in isolation.

John: Yeah. And that’s what we’re going to get into here in the panel of methylation genes that we look at in our nutrition plans. Just to play devil’s advocate, and we get this kind of these… Some of them are fair. I think it’s also fair to say that some of the comments we get are kind of science trolling sometimes on these issues because they’re submitted anonymously and they’re kind of like, you know, sort of like from a gotcha sort of vibe. Having said that, I think it’s important to point out that 23andMe as I believe the biggest sort of consumer facing genomics company has said, “Look, don’t worry about MTHFR. We think that MTHFR is unproven. There’s a lot of stuff that’s circulating out there, but we don’t think it’s a big deal. It’s been linked to all sorts of things from blood clots to cancer to autism. And at the end of the day, there’s just not enough out there on MTHFR.” Having said that, I think the issue is not even MTHFR in and of itself, it’s the clues that MTHFR can give you in your lab work to see whether you have an issue. And one of the big ones is homocysteine.

Aaron: Yeah, we’ve actually got a couple of blog posts on the site, which have got some nice diagrams, which helped make this a bit easier to follow. But I’ll try and talk through it in person as well. So there’s a thing called the one carbon pathway. And that’s where your body takes in folate. And that’s the cycle that the MTHFR enzyme sits in. And that’s basically processing that folate and trying to get to the usable state of methionine. And one of the steps that it goes through is it requires the conversion of home assisting to methionine. That’s the process of generating methionine in the body.

So if you have an MTHFR polymorphism where you have produced activity, you can see that you’re gonna have a store in this pathway. And the amount of homocysteine that you’re gonna be able to convert to methionine is going to be reduced. And so that means that homocysteine is going to pull in the body. So obviously, we want a little bit of homocysteine in the body. It’s an important source for both methionine and cysteine, you know, two key amino acids that are important in lots of processes. But what we don’t want is a lot of homocysteine in the body because its associated with a lot of negative health outcomes. And the most important of which is an elevated risk of cardiovascular disease.

And this has been shown across several different studies, including quite large meta studies now, which is sort of analyses of lots and lots of different studies all together. And they show this effect. The strength varies considerably. So some studies report a really strong effect, others report a weak one, and some report not at all. But the general trend is that too much homocysteine is associated with an increased cardiovascular risk.

John: Okay. So the trend line science-wise for 1298C, which is one of the two we talked about, that’s kind of headed in the opposite direction. They’re sort of thinking that that might not be as important as they had previously thought.

Aaron: I think it’s still important, but I think it was probably given too much importance. So when this all started, you know, people first started looking at nutrigenomics. These are the two snips that people are really interested in. And everyone was really, you know, trying to push both of them. And I think the evidence, it’s just never been quite as consistently strong for A1298C, whereas for the C677T, although there are some sources out there which show negative effect or no effect is more consistently strong for that particular polymorphism.

John: Okay. So I think the takeaway there is if you find out you have an MTHFR snip, you know, mutation, whatever you want to call it, and you’re like, “Okay, don’t panic. There’s a few steps you might want to take. One I think is you go to an advanced lab, like a Boston Heart Diagnostics, or a Cleveland HeartLab, if you can find a doctor to write you one of those scripts. And you go or you might not even have to. I’m not familiar with how common homocysteine testing is in the States. I think it is usually part of an advanced lab and you go and you get your homocysteine levels tested. And I think getting your homocysteine levels tested should be kind of a nice way of determining at a foundational level, whether this MTHFR mutation is affecting your wellbeing.

Aaron: Yeah, definitely. I mean, that’s the place to start. Because you can have…like I said, those that 30% to 70% variation in the effect, even if you’ve got this snip that reduces the MTHFR activity, there’s a 30% to 70% variation in that effect. So you might have it, but you might be, you know, one extreme or the other. And so the most important bit is to actually go and get that physiological test and see what your actual homocysteine levels are in your blood. Because then that can inform whether you actually need to think about this or whether you can just, you know, you have the mutation but it’s not doing anything in particular to you. And if it is, then that’s the sort of time where you can use the nutrigenomics to target because you know which particular enzyme is affected and the things out there that can specifically target these enzymes rather than trying to hit the whole pathway at once, you can be quite selective with what you’re using.

John: Sure. So at the end of the day, what we know in a pretty concrete way is…to repeat what Aaron said, MTHFR, the remethylation of homocysteine to methionine, and that process is dependent on B vitamins.

Aaron: Yeah.

John: It could be that you’re not metabolizing B vitamins in a way that’s as effective as some others. And that could cause this whole homocysteine methionine issue to pool. And that’s the best science in terms of how you know that your MTHFR polymorphism is causing you issues. It’s not to say that there will not be ones in the future that will be discovered. Well, Aaron, sorry, go ahead. You want to add to that?

Aaron: No, I mean, I was just gonna say exactly that. It’s always about the genetics can be an informative tool, but you always need to see it physiologically as well. Because, you know, there’s always a lot of variation with these polymorphisms.

John: Yeah. And it’s something we talk about also just in these lipid conversations. You could have on a Gene Food matrix, you could have certain snips that are associated with reduced, you know, ability to deal well with certain types of fats and maybe you get your lab done and labs and you’ll find a little bit more fat than what your genetic report would indicate. I think that for certain markers, it’s probably unlikely but at the end of the day, the end point here is using the genetics as the foundation. “Okay, boom, I have this MTHFR first snip. All right, let me go see what homocysteine looks like. If my homocysteine is low, then I’m probably getting adequate folate and I appear to be not having such an issue with this pathway.” On the issue of the B vitamins, though. So let’s say your homocysteine is high. That means you’re going to want to be looking at potentially supplementing with B vitamins? Like what does that look like, Aaron?

Aaron: That mean so before you knew about polymorphisms, if you saw that your homocysteine was high, one of the really obvious things that you might think of doing is that, yeah, you’re folate deficient, you’re not being able to process enough folate into the methionine to convert the homocysteine into methionine. You’re not getting that process going. So the obvious thing would be to add more folate. But if you’ve got one of these polymorphisms like the C677T, adding more folate it’s not necessarily going to do anything. It’s just because the enzyme, it’s there, it’s functioning as fast as it can. It’s just not being able to process it through.

So if you find out you have one of these mutations in MTHFR and you find out that your homocysteine is elevated, then you can use vitamin B2 to target specifically MTHFR because as an enzyme, it needs this victim and as a co-factor to work efficiently. So ensuring you have an optimal dose of vitamin B2 can activate MTHFR to its maximum capacity, and hopefully start to, you know, keep the homocysteine cycling into methionine. But there were a couple of other polymorphisms and other genes as well that can be quite interesting that you can use to convert homocysteine down into the molecules as well, which I can go into. If you want now, we can move into.

John: We’re going to get to that in a sec. But I want to just…so you have the elevated homocysteine, you’re looking at vitamin B2, are you not looking at Methylfolate? Are you not looking at methylcobalamine, basically, methylated versions of vitamin B9 and B12, just B2?

Aaron: Yeah. So you can go for B2 to target MTHFR specifically to ensure you’re getting enough of the actual active folate like you say, then you can also supplement with Methylfolate. That’s basically the what the pathway is trying to produce at the end is that Methylfolate early. So rather than sticking in low to the folic acid overloading the pathway, you can just skip the pathway out and give your body what it needs in itself, which is Methylfolate. So B2 and Methylfolate together would be a good combo.

John: Yeah. So basically, you have the situation where, okay, the B2 is going to hopefully help the activity of this enzyme and kind of give it a little more boost in the co-factor department. And then you can also look at something like Methylfolate, which is basically a vitamin that comes in a metabolic stage downstream, it’s already methylated for you. And you can take that and that can give your body some of what it needs. Aaron, you’re saying that you can just also…so let’s say it’s a 30% conversion and I think that could also mean just like loading up on an super extra on the leafy greens, dark leafy greens, all that as well. It seems as though even though the conversion pathways, for lack of a better word, clogged, you’re still going to get some more of that through if you’re really take taking a greater look at getting dietary folate.

Aaron: Yeah, definitely. And I think, you know, a lot of foods out there are fortified with things like folic acid. But if you actually eat well, it’s quite possible to get natural folate, like you say, talking about the leafy greens and things like that into your diet, which could probably help the majority of people because those foods also contain a lot of other beneficial stuff. It’s not going to be a bad step to take.

John: Sure. Yeah, it’s unlikely that eating more leafy greens is going to have any downside. And that is something that people are going to want to consider because at the end of the day, you have to be really careful taking these methylated B vitamins. And I think before we get into these other markers that you want to talk about that kind of round out part of the picture for the methylation cycle, I do think it’s important to tell people about some of the research that’s out there, the links taking supplemental Methylfolate and supplemental B12 to an increased risk of cancer in certain populations.

You did a chart, Aaron, that we’re going to link to in the show notes that’s an awesome visual chart. And basically, it seems as though the folate cut off is 800 daily micrograms, and for B12, it’s 400 daily micrograms. And the thing that’s ironic about that isn’t a lot of the supplements, they’re just throwing a ton more of both of those nutrients at you on a daily B vitamin complex. And those thresholds are above what some studies show increases your risk for cancer. So how do people make sense of all this?

Aaron: I think the doses that some supplements you see are absolutely crazy. I mean, the other argument is that you’re not absorbing all of that. You know, the vitamins that you’re taking in, a lot of that probably just passing straight through your body and isn’t being absorbed. But some of those doses are really, really high. And like you say for B12 in particular, looking at the research out there, there is quite high risks of developing cardiovascular disease or cancer, if you start exceeding that dose of 0.4 milligrams per day. And it gets even worse for people, you know, if you’re a smoker and you’re taking these B vitamins, there’s a really, really strong effect with developing cancer.

So it’s definitely something that if you’re going to start supplementing with B vitamins, possibly look at trying them individually. And that gives you better control of the dose that you’re actually taking rather than having to take a multivitamin with a set dose, you can target the genes that you’re particularly interested in and the doses that you’re happy with.

John: Yeah, starting small. Dr. Ben Lynch, who is a big in the nutrigenomics world, he’s written a blog post that I believe is pretty popular about Methylfolate side effects. You know, taking these methylated B vitamins, just like any supplement, can cause side effects. And if you’re mega dosing, it’s not a great idea. This is another thing just as an aside that I think is interesting for like the vegan world because the vegan world is pretty well aware of the fact that they’re going to have to…if you’re going to go strict vegan for a long period of time, it’s not a controversial point to say that you’re going to need to take B12. Okay, so you’re going to take a B12 supplement.

Now, is a B12 supplement going to cause you to develop cancer in and of itself? No, I don’t think so. Is there a good, credible science out there across a number of different studies that shows that it might increase your risk for certain types of cancer, especially if you’re taking these mega doses of B12? That’s where I wonder to myself, just thinking out loud, are you not just better off just eating a piece of wild fish every so often or, you know, having a couple of eggs maybe a couple times a week or eating a sustainably raised piece of beef?

I know there’s probably a few vegans listening that find that point objectionable because they’re saying, “Look, this is an issue not just for my own personal health but of animal rights. And to that I’m not prepared in this MTHFR podcast to comprehensively, you know, go through all those different debates. I am saying, as Aaron has pointed out, that there are risks associated with taking these B vitamins in high doses. And people need to be aware of that and make decisions based on what the best research shows.

Aaron: Yeah, I definitely agree with that. I mean, I think the other thing is that if you’re following a vegan diet or any of these diets, like we’ve said before, you’re probably better off than 99% of the population, you just don’t care about this stuff at all. So if you are following a vegan diet, you’re already halfway there, you’ve taken care of what you’re eating, you’re really observing what you’re eating. It’s not a big deal to actually just double or have a think about B vitamin intakes as well alongside that. Don’t just go for the highest dose because, you know, you need to take it. Actually think about what sources you’re going to be getting from your food, what sources you can get from supplements, and just try and manipulate your diet that way. And then that could be more beneficial and maybe help you reduce the dose that you have to take as a supplement.

John: Yeah. I mean, one of the things you could look at is doing like a Spectra Cell. Spectra Cell is a micronutrient testing panel. I think it’s like a couple 100 bucks. You could look at something like that. I don’t know that a lot of these nutrient tests that measure in the serum and the actual blood are always that reliable because you’re not actually looking at the nutrients that are sort of making their way into the more important parts of the body. Is that right, Aaron? What’s your take on serum levels of B12?

Aaron: I think because they’ve not really been correlated with, you know, let’s say, the bits where it’s actually required for action and things like that, then we can’t…it’s often difficult to say, “Well, is it just because this person happens to have a high level of B12 in the serum?” It doesn’t actually mean that they have high level where they actually it needs to be. They need to do those tests so really sort of correlate it. But I think people are doing it. It’s, you know, one of the things about people getting these tests out there was that the data sets get ever larger. And once you start getting those data sets and combine it with other tests, you can start to get that information. But I don’t think it’s quite there yet.

John: The nutrient deficiency testing world does seem to be not all that accessible to most people. And I think that’s one of the central ironies is that, you know, what we’re left to sort of resort to are the opinions of, in most cases, partisan nutrition commentators both on the side of, you know, different, more paleo movements and then partisan commentators on the vegan side. You go and you listen. We’re talking about veganism right now because of the context of B vitamin supplements. You go and you listen to some of these people. And just like anyone else, there’s some misinformation that’s spread out there.

And look, I’m not saying I’m the arbiter of all truth. I’m sure that I am unwittingly…you know, there’s things that I’m saying that aren’t always 100%, you know, perfect either. But I hear things that are sort of basic stuff like, “Oh, you can get all the DHA that you need from eating hemp seeds.” And so people are kind of going forward on that basis assuming that they don’t have nutrient deficiencies. And in some cases, they’re actually going to have really severe nutrient deficiencies. And so I think testing and paying attention to some of these issues can really enhance the value of a vegan diet and make sure you’re feeling amazing, like Aaron saying while you’re on your vegan diets. But that’s kind of the point here.

Segue to CBS genes and some of these other genes we look at on our methylation panel, MTHFR ties into methylation. You wanted to talk about a minute ago, Aaron. So what are some of these other pathways people should be aware of that sit alongside MTHFR?

Aaron: So you’ve got that one carbon pathway that I talked about, which is MTHFR and that’s sort of part of that pathway resulted in the conversion of homocysteine to methionine. The actual enzyme that’s doing that conversion is called MTR. So we have that on our website. So that’s methyl that try to folate homocysteine methyl translates reductase to give it its full name, and sometimes actually known as methionine synthase reductase to give its short one. So there’s a polymorphism in there that’s associated with an accumulation of homocysteine again because it’s thought that the actions of that enzyme are reduced. And that one’s known as A66G, that particular polymorphous.

So what we can do with that one, it’s quite nice, is that’s a B12 co-factor enzyme. So we can supplement with B12. And hopefully, that can start increasing the amount of homocysteine being converted to methionine. And linking back to what you said, that’s one of the ones where you would actually need Methylfolate in present to provide that source for the methyl groups to allow that conversion. So, again, if you’re going to look at targeting that one, you’re going to want to have Methylfolate in the system as well just to keep that pathway spinning. The problem with that, obviously, is that you’ve just alluded to as well as the B12 is one of the vitamins that can be associated with an increased cancer risk. So if you are going to look at that one, it’s one of the ones that you want to go up at a slightly lower dose, start working up. Just target your dose and get the maximum amount of effect, but the minimum amount of dose is probably the best way to look at it.

John: For what it’s worth, which I think it’s worth something only to the extent that I’m doing something that’s tailored to sort of my own system and we would all encourage everybody to do the same, when I’m taking…I do take methylated B vitamins on occasion. And when I do, what I’ve been doing lately is I have…we can link to this in the show notes. There’s a product made by Pure which has pretty conservative dosing to begin with. And I’ll just take half of it and just pour it out. And then I’ll just take half a capsule. That’s what I’ve been doing. I just don’t want to take…I’ve zero interest in taking some massively high dose of B12. And also, you know, I’m eating pastured eggs and I’m eating wild salmon and things like that, too. So, you know, I’m getting that from food as well. So MTRR is sort of the…I think of that as the B12 you pointed. That’s another thing that can have this issue with methionine. What about the CBS sulfur genes?

Aaron: So yeah, so that methionine cycle it converts homocysteine to methionine, that’s one aspect of it. But homocysteine can actually also be processed into another amino acid that the body needs, which is called cysteine. And the enzymes that do this are known as CBS or cystathionine beta-synthase. And this is another way that you can basically clear homocysteine, and there’s actually a couple of snips in here. There’s one that’s really rare, which is called G1338. And the A allele of that is actually associated with reduced CBS activity. So if you reduce the enzyme activity, you’re going to get less homocysteine being converted into cysteine. And you’re going to have homocysteine accumulate.

John: Right. Okay.

Aaron: And there’s one that’s a bit more common, which is known as T833C, and the risk allele of that one is C, and that is also associated with an accumulation of homocysteine. But in this case, although it’s more common, they don’t actually know the exact mechanism that would lead into that. So we don’t know because the enzyme is not working as well, or if it’s some other mechanism. And the nice thing with these is, again, they need a co-factor, and in this case, the co-factor for these is it’s vitamin B6. So this is one of the ones where you can supplement at reasonably high doses. So I think our cut off that we would sort of recommend is keeping it below about 10 milligrams per day for B6.

John: That’s what a bunch of the supplements have is they have fairly conservative dose of B6. I would say just there’s a good evidence out there that if you take too much B6 it causes nerve damage. So it’s another one. I wouldn’t just go out and buy a crap load of B6. I mean, B6 is also a diamine oxidase co-factor, though, if you have issues with histamine, you want to make sure you’re getting plenty of that. But I don’t know. So you say 10 milligrams a day, Aaron, for the B6?

Aaron: I think that’s the upper limit that you can get away with a lot less. So I think there’s been some studies out there that showed a dose of about two and a half milligrams per day is well tolerated and provides pretty much as much as the body needs so you can get away, I would say. And I would say start even below that recommended daily amount, that level of 2.5. I would go in at the 0.5 milligrams. And like we’ve sort of said in another podcast, keep a food diary. See what effect that dose has. Try it for a week. And then if you don’t think you’re having any effect, just increase it and, you know, just always keep that food diary to see what effect you’re having. And then try and see what dose you reach before you start seeing the effect because if you go in at that 10 milligrams having never had anything previously, I can almost guarantee that you’re going to have a quite a bad time on it. And you’re gonna have a lot of side effects from a dose like that.

John: Yeah, I just as in my…I tend to do dumb shit sometimes. You know, it happens more than I would like. And one of the things I did with supplements is I took a whole bunch of B6, yeah, maybe a year and a half ago, and yeah, I felt pretty bad. I initially felt good, but I felt pretty bad after taking what it were pretty large doses of B6. The thing that’s weird about that to me is that a lot of this standalone B6 supplements, like the one dose of one capsule is like 30, 40 milligrams often, 20 milligrams, stuff like that.

Aaron: Yeah. Like we say, some of the doses that they come in, it’s crazy. And I guess that’s why the capsules, maybe people are moving more towards liquid doses because then you can actually have really exact control of the amount that you’re going to take every time, you know, even down to the sort of the micro ground level. You can say this is exactly how much I want to take and then you can take that. It’s not dictated to you by what the capsule has in it.

John: Yeah. Great point and B6 with the CBS stuff. CBS is one of the genes that the people that are interested in nutrigenomics and some of the people that order plans from us they want to know about. You pointed out the low CBS activity is another way that you could get high homocysteine. So it’s another reason to check homocysteine. And then elevated CBS activity is the flip side of that is high ammonia. Is that correct?

Aaron: Yep.

John: Okay. And those are the people that are actually really sensitive to sulfur donors and sulfur donor supplements because they’re hyper converting.

Aaron: Yeah. So those guys might want to have their ammonia levels assessed if you have an overactive CBS and you actually processing that homocysteine through to cysteine. And then the other downstream pathways from that, as well, you may want to consider having your serum ammonia levels tested.

John: Yeah. And that’s an easy one to get done. And that’s a cool thing about these genes. As you get the genes, you’re like, “Okay, I have these genes.” And then in most cases, for the well-known ones, there are labs that you can then go get and you can kind of clue in and be like, “Okay, well, I think theoretically I have this up regulated CBS activity. Let me see if I have high ammonia as well or I think I have this MTHFR problem. Let me see if I have high homocysteine. And the labs can give you further clues as to kind of what you might want to do to take some of this stuff and be proactive about it. What are a couple other of the methylation genes that we have on our panel, Aaron, that you think the audience would want to know about?

Aaron: So there’s one that’s not that commonly discussed, which is known as SHMT1, which is serine hydroxymethyltransferase 1. So this actually sits in the one carbon pathway before MTHFR. You don’t see that one discussed as much as other ones partially because it doesn’t have a strong as an effect. But it’s also, I think, because MTFHR is such a sexy gene and topic for people that they tend to focus on that one. So we look at one particular sniper now, which is known as C1420T and it’s the T allele is the risk one in this case. And this if you carry that T allele, it means that your enzyme changes its localization in the cell, which impairs its ability to convert the folate that’s coming in into the substrate the MTHFR needs to process.

So again, it’s just another way of clogging up that pathway. So, you know, if you have a defective enzyme or a less functional enzyme, you’re not providing the substrate for the next step in the pathway. And it just causes the whole pathway to slow down or grind to a halt. And again, you know, because these are all for B vitamin tied in this one SHMT1 is B6, is the co-factor again. So that sort of ties in with the CBS one. If you’ve got snips in both of them, you can use B6 to target both of those genes as well.

John: Yeah, so it all comes back to some of these genes amazingly. I think of it as amazing because there’s growing up in a traditional sort of medical environment, not that my parents were doctors, but just being around doctors, there is a sort of a very skeptical eye that’s towards using supplementation for different things. And I think rightfully so. But in this case, these B vitamins are the co-factors for these enzymatic processes. And if you have reduced enzyme activity because of some of these snips, then if they’re dialed in right and they’re taken at the right doses under the right circumstances or you’re getting food that’s higher in B vitamins, you actually could get some benefit from this. Although I did see some stuff out there, Aaron, that even when homocysteine levels come down based on B vitamin supplementation, it does not always remove the risk for heart disease.

Aaron: Yeah. I mean, the homocysteine is like an inflammatory mediator. It generates an inflammatory response. And that’s why it’s associated with cardiovascular disease. It’s damaging the arteries and it’s leading to the sort of, you know, the classical symptoms of cardiovascular disease. And that’s obviously a long-term thing. So if you’ve been living with that for a long time, then the damage has probably already been done and it’s not very easy to reverse that.

John: That’s a great point.

Aaron: So the I guess I’d try and catch it early before you’ve done a lot of damage and try and bring those homocysteine levels down earlier rather than later.

John: I’m envisioning in my future some scenario in the coming years where I have had my kids genetically tested and in addition to giving them like a healthy breakfast and sprinkling like 1 milligram of vitamin B6 or something like that. I don’t know what that’s gonna look like, but I’m envisioning this future supplement regimen. And I think that speaks to how important it is to kind of know this stuff right away because if this isn’t inflammatory pathway, it’s something you can reduce. That’s pretty cool.

Aaron: Yeah. I mean, you’ve kind of hit the nail on the head there. We are still paddling on the shores here really with, you know, these nutrigenomics stuff. We’re only looking at a tiny number of polymorphisms, even though we actually look at quite a large number on our nutrigenomics report compared to the number of bases that there are in the genome, it’s a tiny, tiny amount. But we get more knowledgeable every year. And I think you’re probably right, it won’t be that far off that we have a really personalized nutrition plan, probably from birth because you get, you know, genetic tested at birth. And they say, “You need this, you need that, you need the other.” And that’ll just be the way it is. We just have a very targeted and specific diet.

John: Well, that’s exactly…I’ll tell you, in terms of the number of snips you report on, I mean, your system that you created is amazing, the scoring system. The thing that’s really cool, I don’t even know if I’d even gotten chance to tell you this, it’s just brand new, but it looks like now we’re actually finding a lab partner that we believe in that we can work with. And we’re going to be able to roll out a little more extensive number of snips because what’s been happening is, you know, 23andMe will…you know, we take right now raw data from Ancestry and 23andMe. And 23andMe will decide from version to version which snip they want to report on.

One of the ones that they’ve removed that I think is really unfortunate are some of these histamine genes, AOC 1 and some of these, because I think that they’re really relevant for people in terms of people food sensitivity and potentially sensitivity to certain locations in certain situations. Although I know that there’s more science that needs to come out on those genes. That’s just sort of me anecdotally speaking of customers and kind of digging in on some of the stuff. I think we’ve done a pretty good job with methylation and MTHFR. I wanted to do a little bit of genetic roundtable to close off the show because there’s some questions to wrap up. Some people from the very first episode we did on apoE4, they wanted a little more concise…you know, that was done in the context of ketogenic diets, and they wanted a little more concise thinking.

We got one nutrition plan customer in particular email and said, you know, “Tell us a little more about apoE4 in terms of if I have one, if I’m apoE3/4, what does that mean? If I’m apoE4/4, what does that mean?” And so maybe we should dust off some of that from our first show and kind of talk to the people a little bit about apoE4 dietary issues there. I think the big one is this distinction between the ketogenic diet after you’ve developed Alzheimer’s and having apoE4, and then the wisdom of the ketogenic diet as a preventative measure for staving off Alzheimer’s with apoE4.

Aaron: Yeah. I mean, that’s really influx because there’s some really cool science out there that’s showing really interesting stuff in animal models where if you’re on a ketogenic diet, it can be protective against developing Alzheimer’s. And even if you actually have developed Alzheimer’s, it can slow the development of the disease by switching to a ketogenic diet. And, obviously, that’s of interest. People who have the apoE4 polymorphisms because there are an increased risk of it. But some of the sort of early work coming out there is actually showing if you have that, you know, if you’re an apoE4 carrier, then that ketogenic switch doesn’t necessarily work as well for you as it does for the general population for those with apoE2 or apoE3.

So it’s kind of it’s a little bit in…I don’t want to come down too hard on one side or the other at the moment because I know a lot of people are going to be interested in trying and the results in the animal models are really exciting. And it’s always just difficult to do these tests in a sort of an older population where they’ve lived…you know, it’s trying to model this over to a human population over time is really difficult. But my take would be that if you have the apoE4 polymorphisms, we would recommend that you don’t go on the ketogenic diet because its associated with other cardiovascular risks. But obviously, if you want to do it for the protective effect, just be aware that, you know, maybe it’s not actually helping as well as you think it might do.

John: Yeah, Aaron is a consummate diplomat. I mean, he’s a very diplomatic guy and he’s a scientist. I mean, his job is not to come out and to take position. So what I’ll do is I’ll say what my position is and that is that if you have apoE4, then you really shouldn’t go on a ketogenic diet, especially ketogenic diet that’s high in saturated fat, because it seems as though there is evidence out there that for people to have apoE4, you could have this very inflammatory reaction to a diet science saturated fat.

If you still want to try the ketogenic diet and you have apoE4, of course, all this is against the backdrop of hopefully you’re working with a physician and the advice of your physician trumps the general principles that we’re talking about here, you know, obviously. But if you say, “Okay, you know what? There’s this animal studies that are out there. I’ve been listening to a lot of people in the ketogenic world, I think I do want to try this even though I have apoE4, I have an easy, easy way of handling this for you to get Aaron’s point in. Take your blood work prior to going on ketogenic diet, look at your LDL particle, look at your LDL cholesterol, look at your levels of triglycerides, look at some of the markers, like your C reactive protein, these different markers, and then go on a ketogenic diet for a month and then see what they look like.

And if they look better or if they look neutral, then you’re kind of one of these people in the Retterstøl study that we talked about in the first episode who might have a complement of other genetic markers that are offsetting the risk associated with the ketogenic diet and your blood work looks good. And, you know, maybe in that case, you’re okay. But if you’re looking at what some of the really, really badass nutrition commenters out there who are also familiar with genetics are doing, having an apoE4 polymorphism, Rhonda Patrick, Dr. Rhonda Patrick, super smart. She has apoE3/4. She is not following a ketogenic diet, instead of what she’s doing is she’s making sure that she’s getting a diet that’s very high in omega-3, high quality omega-3 fats because of the fact that, look, the brain is made up of DHA and that that’s her strategy. And then if you have Alzheimer’s, I would say, you know, if you’re unfortunate and you’ve already developed in that case, Aaron, there’s better evidence that it’s actually beneficial, correct?

Aaron: Yeah. So if you’ve developed Alzheimer’s or you know, you’re at the early stages of disease, evidenced that ketogenic diet is beneficial overall, for everyone, regardless of the APOE genotype. But the stronger effect seen in those with an apoE2, on apoE3 as in may see the best beneficial effects. If you’re apoE4, you’ll still see a beneficial effect, it’s just less so than the other two versions.

John: Okay. And I mean, in our reporting, if you have apoE4, you get knocked down. It’s very likely you’re going to get knocked down a fat category in terms of a lower saturated fat category.

Aaron: So we use apoE4 to pool people. It’s one of the ones that we actually use to pool people and maybe even block people from certain categories because we think of it as important and relate to the saturated fat, like you talked about.

John: Yeah. And, again, don’t necessarily take my word for it, you know, go read and listen to different sources and listen to some of the people that are the plant-based advocates and listen to some of the people that are the high fat advocates. They’re very smart people on all sides of this debate. You know, ultimately, you’re going to have to make the call. This is “The GeneFood Podcast.” I’m the host of the podcast. My take is if you have apoE4, just don’t go on a high saturated fat diet, just eat your wild salmon, eat your salmon roe, cut out the omega-6 fats and just basically have like what would amount to a plant-based diet and making sure that you’re getting enough omega-3 fats, which means that basically, Valter Longo’s protocol. I think that’s a much better protocol for apoE4 than going on a high fat diet where you’re eating cheese, you know, for breakfast and you’re eating a ton of coconut oil. So, again, that’s the best we can do in terms of what’s out there in apoE4 because this is all still evolving.

Aaron: Yeah. And I think you asked as well or you said someone had asked the difference between having two copies of apoE4 or just having a three and a four combination? So I think if you’re homozygous for apoE4, so you have two copies of it, I think the risk of developing Alzheimer’s is about 14 fold, compared to the carriers of two, three alleles. And then if you’re heterozygous, so you have an apoE4 and an apoE3, it’s a three or four-fold increase. So it’s quite a bit less. But, you know, that’s still quite a dramatic fold increase in risk.

John: Yeah. No, it’s a big, it’s a big increase in risk. That’s why people are so afraid of getting apoE4, but I know in conversations that we have privately, you know, it seems like, you know, there’s this issue of, yes, I have this, but then there’s also these other genes, you know, your LDL receptor genes, maybe your PCSK9 genes, some of these other cardiovascular genes, FTO, that if you have a good genetic background there that it could sort of offset some of the risk of that.

Aaron: Yeah. So, I mean, looking at my genetics, that’s kind of the category that I fit into. I have one version of the apoE4 allele and then the other being a three. But looking at the other sort of genes in my fat metabolism pathway, I could possibly work a ketogenic diet. It’s not personally for me a ketogenic diet. I’ve tried it and I didn’t really get on with it. But I could probably get on with it from the genetic standpoint, and that I can process saturated fat reasonably well. I should be able to get a reasonable intake of omega-3 and not overdo my omega-6 intake. So there are people out there who will actually benefit from it, you know, obviously, if they like the diet themselves, as well.

John: Sure. But at the end of the day, you gotta test because, you know, if you’re going to do it…I think under any circumstances, if you’re going to do it, you need to test. But if you have apoE4 and you decide to go down that path because of other robust fat genes, great, that’s your call working with your doctor, just make sure that you’re testing especially your LDL particle count. And if your LDL particle count looks good, then just like with homocysteine and MTHFR, then you know, you’re probably clued in that that’s maybe a healthier reaction for you. And if it doesn’t look so good, then you want to check out this study called Retterstøl, which was published in this journal called Atherosclerosis last year, and it talks about this incredible variability between people that are put on high fat diets. Some people have really bad stuff happen to their lipid markers, some people’s lipid markers look just fine. It’s a great way, you know, to figure out if it’s working, I think.

Aaron: Yep, definitely, definitely agree.

John: So we’re talking about the omega-3 stuff. FADS1, this is a good thing to add into our genetic roundtable considering we’re talking about omega-3 fatty acids. You found just some stuff that’s like some of the coolest research I’ve seen since I’ve been looking at nutrition and medical issues, Aaron, and FADS1 stuff.

Aaron: So we kind of touched on it a little bit, you know, about the facts that we can intake omega-6 and omega-3 and how we’re shifting towards an omega-6 in our diets and most of Western diet, and especially certain diet types, like a vegan diet can be quite omega-6 heavy and low in omega-3. And this is important because maintaining a good ratio between the two is really important and ensuring we get the good products of the processing through the body. So one thing that’s really interesting is both the omega-6 and omega-3 fats share the same processing pathway. And one of the enzymes that we use is the FADS1 that John talked about.

And ultimately, these, you know, the Omega-6 and omega-3 fats are processed. Omega-6 going into arachidonic acid or AA and omega-3 going into…I can Never say this one. It’s hard to say. The acronym EPA and then eventually into DHA. So EPA and DHA are the ones that we really need. They’re the ones often people talk about them as brain food, they’re the ones that you need for really good to maintain neurological health. By sharing the pathway, though, what happens is if you shift too much to the omega-6, so you have loads of omegA-6 and not much omega-3, then the omega-3 is not going to get processed as efficiently.

And you’re not going to end up with any of this EPA or DHA in your diet. And you’re going to end up with more of the arachidonic acid. And that’s bad in itself because you’re not getting the DHA. But that arachidonic acid is also associated with this pro-inflammatory state. So if you have too much of it, you can start generating a pro inflammatory state in your…and again, that’s associated with things like the neurological disorders, cardiovascular. That pro-inflammatory state is something we want to avoid. So FADS1 that we talked about fit really nicely there.

John: Yeah, it did and I think, you know, that’s a great point, especially because we just got off of this conversation about apoE4. You’re going to have some segment of the people that are listening who are going to probably be more inclined to go on a plant-based diet. But the problem is they’re going to listen to commentators out there in the vegan community who I think are very well meaning. But one of the facts that is being teased out by this genetic research is that people don’t convert the short chain omega-3 fats from plants into the EPA and DHA that the brain needs as Aaron just said.

The conversion is actually highly variable based on genetics for a few reasons. One of which is the omega-6 fats and vegetable oil, for example. Those are converted, as Aaron said, into inflammatory stuff, arachidonic acid. But the same pathways that are used by the body to convert what’s called alpha linoleic acid, which is the omega… When you hear people say, “Oh, well, hemp seeds are chock full of omega-3 and walnuts are chock full of omega-3.” Well, no, they’re not. They’re chock full of alpha linoleic acid. And the body converts the alpha linoleic acid into the EPA and DHA. I found a study that I’m going to put in the show notes that looked at 19 men who were confirmed in their bloodwork to be low on EPA and DHA.

They gave them a ton of dietary alpha linoleic acid. And they looked at, I think it was like five, six weeks later. Their alpha linoleic acid levels went up, their EPA levels went up because the conversion from alpha linoleic acid to EPA seems to be more robust than the conversion from alpha linoleic acid to DHA in some people. Their DHA levels went down. So you get the person who’s on the plant-based diet because they’re apoE4, they’re trying to have an anti-inflammatory diet, they’re scared of saturated fat. They think they’re getting their omega-3 fatty acids from hemp seeds. They’re one of the people that’s getting almost no omega-3 fatty acids from hemp seeds, including DHA. They become DHA deficient. Forget about 20, 30, 50 years from now developing some terrible chronic illness. DHA deficiency is linked to, you know, in the short-term anxiety, depression, different mental issues, you just might not be feeling all that fantastic. And that’s just a point that I’ve become absolutely obsessed with, frankly.

Aaron: Yeah, I mean, you kind of hit it on the nail that those sources of omega-3 are often actually also rich in omega-6. And so you’re just overloading the pathway with the omega-6, which is what you kind of you don’t want too much of but, you know, trying to get that omega three without the omega-6, it’s quite difficult, really.

John: On a vegan diet. It is. Yeah, because at the end…

Aaron: On a vegan diet, yeah.

John: …at the end of the day you have hemp seeds. They have linoleic acid, which is the omega-6, then they have the alpha linoleic acid, which is the omega-3 in almost equal quantities in that food. So you’re never getting a pure shot at the omega-3 fats EPA and DHA, you’re only getting shots at the precursors. And the precursors are basically fighting. So like it gets in the body and there’s just like metabolic war where the linoleic acid fights with the alpha linoleic acid is like a war to say, “No, I want to get turned into arachidonic acid.” “No, I want to get turned into EPA and DHA.” And then what we’re learning based on what Aaron has uncovered is that in certain populations, I carry these markers also in African-American and Mexican populations.

All the studies were done in white people. So now what we know is that African-American populations and Mexican populations carry some of these FADS1 variance, where they take even more of the linoleic acid, the omega-6 fat and they turn it into arachidonic acid which is inflammatory. They used to think that it was a cap of like 2% to 3% of the linoleic acid that you would convert to arachidonic acid. And I think in some of these populations, Aaron, correct me if I’m wrong, especially African-American and Mexican populations, all bets are off.

Aaron: Yeah, it’s a really tricky one because you kind of, like you said, the people with the T allele of the FADS1 that we’re talking about, they have a reduced ability to process omega-3 and omega-6. So, you know, they might not be getting as much omega-3, but they’re probably getting less as the part of omega-6. Whereas those populations with the G allele, they’re going to be converting much more quickly in both cases. So they’re going to get more the omega-3 passing through more of the omega-6. And that’s great if you’ve got loads of omega-3 in your diet because you’re going to get the good stuff that you need. But if you have a diet really high in omega-6 and not so high in omega-3, then you’re going to be pushing all of that through into the sort of pro-inflammatory state. And so it’s just a really difficult balancing act.

John: Yeah, it is. And I think one of the key takeaways, and I don’t want to sound melodramatic, I think of it as almost like a public service announcement. And even Dr. Greger who’s one of these, you know, NutritionFacts.org. He’s obviously a total proponent of plant-based diets for all people all the time, but he talks about, you know, look, you vegans probably should be taking a DHA supplement because of the fact that, you know, not everybody is going to convert these omega-3 fats into this stuff that the brain needs. And the only way to get it is really Algal oil. And you kind of need to take a whole bunch of Algal oil because Algal oil is has actual…it’s not alpha linoleic acid that needs to be converted, it’s actual EPA and DHA.

The problem is, is very funny when you start looking at these Algal oil supplements. You know what they’re made with a lot of the time? Sunflower oil, which I just think is absolutely crazy. I looked at this, I bought some because I don’t really want to be like mega dosing fish oil, I take some cod liver oil, because I’m working on some of these EPA and DHA things. I want to make sure my levels are higher, especially as compared to like arachidonic acid in my diet. And I looked at the back, I just couldn’t believe it. The two that I looked at which I thought were trustworthy brands, they’re both made with like sunflower oil, which is high omega…you know, again, I don’t know if it’s going to be enough sunflower oil to tip the balance. But my understanding is that these omega-6 fats, especially in people that have these variants makes it a lot tougher to get their omega-3 fats.

Aaron: Yep, definitely. It’s finding something that you can get that omega-3 without…I’m sure the nutrient makers will cut on to this and, you know, they’ll start providing them in formats. I’d say without loading them up with sunflower oil as well, they’ll give them in a better vehicle. But for now it’s quite a tricky one to try and solve.

John: For now, I think it’s just if you’re going to stay plant-based, let’s say you’re one of the apoE4 people, subject to what, I mean, you know, your doctor’s advice trumps but DHA is probably one supplement you want to look at because you’re getting pure EPA and DHA. It’s just about the only way. And then I think the other one is, you know, it could be terribly ironic that you’d spend a whole lifetime avoiding saturated fat because of the fact that it would have an inflammatory reaction in your body based on genetics, and instead turned to vegetable oil, which could have just as much if not a more inflammatory reaction in your body. Because, A, the process of making it, the fats themselves are damaged. So you’re basically eating oxidized rancid fat in many cases.

And also, you could have a genetic variant like I do where you’re taking the linoleic acid that’s in that stuff, and you’re making more bad stuff out of it than other people would. And that bad stuff that you’re making is then causing the inflammation that you’re trying to avoid by never eating a steak. So it becomes quite a complicated web, I think.

Aaron: Yeah, that’s one of the ones where it’s good to sit on the fence. Because you can’t really…for this one in particular, you can’t really say go one way or the other. It depends on lots of other things like your dietary intake as well. And, you know, and making sure that you get the right source of it. You can’t just give one bit of advice and say, “Do this, do that,” depending on your polymorphism. It depends on the whole host of other things.

John: Yeah, it sounds like basically what it’s all kind of pointing at is like a custom nutrition plan of some kind that sort of looks at a bunch of different genetic markers and then kind of like maybe ties it into one endpoint. I don’t know. I think that’s maybe where it’s headed.

Aaron: Yeah.

John: Right?

Aaron: I think that sounds like a… Well, the good general advice is that everyone should probably get more omega-3 and try and shift that ratio away from omega-6 towards omega-3. I think almost everyone would benefit from that shifting.

John: Yeah, I think that’s right. I mean, that’s definitely something that I’m working on. I mean, I was opposed to the whole vegetable oil thing because of the fact that I saw that…on some lab work I had I was absorbing sitosterol, you know, not like crazy amounts, but I had higher sitosterol and then I saw this New England journal medicine study that shows that basically Lp(a), which is a particularly atherogenic form of APOB sub-particle will bind preferentially to Lp(a) and that’s what tends to make it really atherogenic is the fact that you have not just the Lp(a) but the fact that the Lp(a) preferentially binds to oxidize basically plant fats, plant sterols. And then so that was already on my radar to begin with. Now that I know that it’s not just that, but it’s the fact that this vegetable oil will, you know, your body just uses it to make bad stuff. I just feel like vegetable oil is like the thing that’s probably caused more disease in the diet than maybe anything.

Aaron: Yeah, it’s that shift away. Because obviously there was the big saturated fats are just bad. You shouldn’t have any saturated fats. And obviously, that meant that people shifted away towards the more vegetable-based fats and probably overloaded the diet in that way. Where’s the true stories that we probably all need a balance of all the various different facts and the actual makeup of that balance will probably vary by person, but we all need some of these different facts in different amounts.

John: Yeah. I mean, I think an easy thing to do to zoom out a bit and have a practical kind of like put a bow on it is I talked about this last episode with Dr. Kahn, you know, get an app like Cronometer. Cronometer is a great app and then really put in what you’re eating. And also if you go out to a restaurant and you eat an omelet, the likelihood is that that omelet was sautéed in vegetable oil. So make sure that you take and add a tablespoon of vegetable oil to your Cronometer data at the end of the day and then just see what is your omega-6 to omega-3 ratio look like and track that for a couple weeks. I think a lot of people would probably be pretty surprised that, especially if they don’t take like an Algal oil or some kind of official supplement or eat, you know, wild, fatty fish that their omega-6 to omega-3 would probably look pretty bad.

Aaron: Yeah, I mean, I know that’s something that based on a lot of the research that I’ve been doing, it’s something that I’m definitely trying to shift as well. Get more of that omega-6 in my diet. And it’s like you say you do forget when you’re cooking or when you go out for a meal and you’ve ordered something that you forget about what how’s it cooked? How is it prepared? What was the oil that was cooked in? And they are quite large amount that you say a teaspoon of vegetable oil is quite a large amount of fat really.

John: I factor it in is like it just I say, “Okay, well, that’s probably a tablespoon of vegetable oil.” I’ve even just…and I just refused to think about it too much because like some of my favorite restaurants around here, like my favorite breakfast places, I know that they’re taking whatever. You know, there’s a place I like where they make a dish called the Hudson scramble, which is like eggs and avocado and a little bit of cheese and like some like, you know, grape tomatoes and stuff. It’s really good. But I have kind of peeked in the back of the kitchen. And I’m like, “Oh, man, they’re definitely…”

Aaron: Well, at least you don’t have full English over there. Because when you do a full English, that just sets your heart racing.

John: What does?

Aaron: Full English breakfast. You know, you can talk about avocados and stuff but a traditional full English breakfast, that’s probably a dietitian, a nutrigenomics it’s a nightmare seeing one of those.

John: Well, like sausages and…

Aaron: A fried sausage, fried bacon, cut bran, fried egg, basically everything fried, baked beans, black pudding, basically everything that’s possibly bad for you.

John: But that’s really good for you. And as long as it doesn’t spike your blood sugar, that’s really good for you. Didn’t you not know that? As long as you’re in ketosis, then you can eat that every day and you’re going to be fine. There’s no science that indicates otherwise. You know that, right?

Aaron: The baked beans take out. The baked beans, it’s carbohydrate source so that the traditional full English, you can’t get into the ketogenic one. You’d have to lose the baked beans and then it becomes something weird.

John: Get the baked beans out of there and everything is going to be just fine. I think that’s the culprit.

Aaron: Maybe if you had sell it that way. Yeah, ketogenic English breakfast.

John: That’s what you really need for the most. That’s going to give you the bang for your buck that you’re looking for, I think. Okay, so, you know, genetics roundtable, kind of a new podcast format. Basically just taking listener questions and kind of walking through our take on some of the genetics. Anything that you would like to say in closing to clarify or reach the people that are good enough to make it this far through such a technical podcast?

Aaron: No, I mean, I think it’s…just to finish it off how we started, the important bit is to realize that your genetics can just be a marker for things that might affect you, but there’s always this huge amount of variation. So the most important bit is where possible, look at the physiology, look at your personal physiology. And if you can do it, track it over time. You know, if you make dietary changes and you have the ability to track the various physiological outcomes that you’re measuring, you know, that’s a really powerful tool because you can see what effect it’s having on you personally. And ultimately, that’s the important bit. It’s not, you know, these studies out there with tens of thousands of people don’t really matter. It’s how you respond to it that matters.

John: Yeah, absolutely. We have it in a blog post. We talked about one of the most famous carnivore dieters, Mikhaila Peterson. And you said this, Aaron, in the ketogenic episode, said, “Look, just because, you know, people say, well, her blood work looked really good and it really did. It looked really good. She’s eating nothing but beef and beef fat. It looks great.” You want to give that a try, you feel good, go for it. Just go and get your labs done before and after. And that’s going to give you your clue as to whether these genes are an issue, whether they’re not.

And it’s also going to give you an idea of, you know, whether your diet is working. And that’s why on our nutrition plans, beneath each section, fat metabolism, histamine, all these certain types of things, we have labs that people can then go and do and kind of check to see if the way they’ve been scored genetically is corroborated by their own individual lab work. So yep. I think at the end of the day, it’s a huge message from all of our shows is just go test, don’t guess.

Aaron: And also give us feedback. It’s great to hear feedback from people who say, “Well, you know, this was surprising. This didn’t work for me, that did work for me.” Because it is ultimately it’s a new field, really. So any sort of things that we can start to feed back into the nutrition plans, it’s always really cool to hear from as well.

John: Yeah, absolutely. Well, one of the things that’s going to be cool is with this new lab that we’re partnering with for the, you know, hopefully by the fall, we’re going to launch. We’re going to have our own testing kit. We have our own lab we’re working with. We’re going to be able to get our histamine genes back, you know, because some of these versions of 23andMe, they have started not reporting and quite as many of the histamine genes and things of that nature. So we’re marching forward too and I think that’s exactly right. Give us the feedback. Let us know how it’s working.

Aaron: Yeah, that’s interesting because I’m one of those people. I’m on the V5 23andMe. So I lost all those the AOC snips.

John: Yeah, and the AOC snips, man, those are near and dear to my heart because I really believe that in some people that lower level and for the listener, the histamine snips, basically, again, it’s another enzymatic process. Certain of these snips are associated with preliminarily lower levels of these enzymes that clear histamine out of your body. And what I have seen in people that, you know, have done our reports and who get a really bad histamine score, they tend to be people that are probably a little bit more prone to food sensitivity, sensitivity to certain locations. If there’s anyone listening, skeptical of that hypothesis, I am certainly not married to it but I will say that uncleared histamine appears to act in a similar fashion to like eating wheat, it produces… Zonulin and histamine, Aaron, is that right?

Aaron: Yes. I mean, it’s the uncleared histamine that…well, histamine responses, hay fever, you know, the allergy response. If you have reduced DAO. AOC1 is the gene, DAO is the protein. If you have reduced activity of that, you’re going to get more history in building up. And it’s not that biggest step to go if you have this histamine building up in your gut and you’re going to be developing food and tolerances, especially if is a food that particularly triggers like a histamine release.

John: Yeah, because all the…you know, we talked about it and we may have to do an episode on it, the commentators out there at the whole histamine issue, it’s like you have a bucket, you can get rid of only so much histamine. Once that histamine fills, it’s going to start to cause symptoms for people. There was a really good histamine intolerance article that was written in the American Journal of Clinical Nutrition, it’s credible, it’s still preliminary, but there are people out there struggling with this for different reasons. And one of the things you can look at are some of these histamine genes to say, “Hey, you know, this might be something that you could have a predisposition for or you might get more easily placed into this bucket of histamine overload based on what’s happening with you.”

Next week, actually, to segue, I’m interviewing a guy named Eric Johnson who’s the godfather of this movement called the locations of fact, who has a huge cult like following. And he is somebody who swears up and down that one of the single biggest determining factors of your health is actually where you are physically located. And they have a theory called, basically it’s like mold avoidance, where they are super vigilant about avoiding all mold in the air. And some of these people claim that it brings them back from the edge of chronic disease.

We’re having him in part because we had such a…there’s a lot of request for him to come on. But when we interviewed Dr. Nathan, Dr. Nathan sort of poo-pooed that movement a bit. And some people were very upset about that. And so I want to make sure that we have on this guy for equal time to talk about that. So that’s going to be all about how your physical location can be a big driver of how you feel. And I think that’s especially true for people that carry low clearance of histamine.

Aaron: Yeah, definitely. I mean, you know, if you’ve got these problems with histamine and you live somewhere where they’re going to be a high pollen count, you’re going to have an issue with things like hay fever more than other people. Food intolerance is obviously a bit more of an interesting one because then you’re getting into the body’s immune system and that’s hyper variable between people. So what causes you to have a food intolerance? The location thing sounds quite cool. I’ll definitely give that a listen and see what it sounds like.

John: Yeah, I don’t think you’re probably going to assign to it the highest of science scores. You know, I would not imagine that that’s going to be like just breaking our science square meter. But having said that, how the hell are you supposed to study something like that anyway? And I think there is that.

Aaron: I mean, location definitely has a big impact. You know, if you live in the middle of a city compared to out in the middle of the countryside, you’re gonna have completely different health outcomes, you know, obviously, that can be negatives and positives to reach. But, you know, location even at that level.

John: Absolutely. I mean, well, you’ve talked about this concept of like, well, just straight away. If you have a pollen allergy and you’re sitting in an environment where the pollen count is super high, your immune system is releasing in, there’s an inflammatory cascade that’s being released from your mast cells. And if that continues for long enough time, that can cause inflammation in the body for sure.

Aaron: Yep. Yeah, definitely.

John: But then there’s also the idea of maybe in the future… Well, we’ll wait for the episode to do that. But anyway, good stuff. Well, again, Aaron, you know, these are good episodes. Glad to have you on and I’m sure to see you again in the very near future on another episode. Thank you for your expertise. As always, I hope you have an awesome weekend.

Aaron: Cool. You guys too. Enjoy the rest of your day.

John: All right, buddy. Sounds good. We’ll talk soon.

Aaron: Cheers. Bye.

John: “The GeneFood Podcast” is our attempt to synthesize the latest developments in the fields of genetics, nutrition, and medicine, and offer you practical tips and stories you can use in your own unique health journey. If you enjoyed this podcast, you can find more information online at mygenefood.com.

John O'Connor

John O'Connor is the founder of Gene Food. Read his full bio here.

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