Below is a transcript of the interview if genetic testing is helpful or harmful:
Dr. Hedberg: Well, welcome, everyone, to “Functional Medicine Research.” I’m Dr. Hedberg and very excited today to have Dr. Tommy Wood on the show. We’re gonna be talking about genetics and genetic testing. And Dr. Wood is a research assistant professor of pediatrics in the University of Washington, Division of Neonatology. Most of his academic work is focused on developing therapies for brain injury in newborn infants but also includes adult neurodegenerative and metabolic diseases, as well as nutritional approaches to sports performance. Tommy received an undergraduate degree in biochemistry from the University of Cambridge before obtaining his medical degree from the University of Oxford. After working as a doctor in central London, he moved to Norway for his PhD, and then to the University of Washington as a postdoc.
So, in addition to his academic training, he’s coached athletes and dozens of sports, weekend warriors to Olympians and world champions. He’s the outgoing President of the Physicians for Ancestral Health Society, a Director of the British Society of Lifestyle Medicine, and sits on the Scientific Advisory Board of Hinson performance, which includes researching performance optimization strategies for Formula One drivers. Tommy’s current research interests include the physiological and metabolic responses to brain injury and their long-term effects on brain health, as well as developing easily accessible methods with which to track human health performance and longevity. So, Dr. Wood, welcome to the show.
Dr. Wood: Thanks so much for having me. I’m excited to be here.
Dr. Hedberg: Great. So, before we got on, we were just talking about a lot of the big issues in functional medicine include, unscientific and unvalidated testing and therapies and things like that. And so that’s why I was really looking forward to this because genetics is something that I’ve never really got on board with as far as testing and treating patients. So, why don’t we lay some bedrock for the listeners? And if you could just let us know, what is the current academic position by scientists on commercial genetic testing for SNPs and the interventions that some practitioners are using?
Dr. Wood: That’s a great question. And having spent a lot of time sort of straddling both traditional allopathic medicine, traditional academic research, and then also functional medicine, particularly with athletes, but also with various clients with chronic health conditions, there’s this real tension between the two in terms of, you know, what’s done and the evidence that supports it. And I think that’s where some of these genetics stuff comes into play. And when I started really looking into this, you see very rapidly that academic geneticists who have been, you know, studying these things for, you know, probably two decades now, at least, since the beginning of the Human Genome Project. The current state of the science would say that direct to consumer tests, single nucleotide polymorphisms are essentially useless in terms of their ability to either predict disease risk or say response to a personalized nutrition or supplement regimen based on SNPs because most, A, the disease risk is usually very small if there is an increase in risk associated with the SNP, and then the vast majority, you know, 99.99% of suggested interventions based on SNPs just haven’t been rigorously tested in any kind of clinical trial. So, if you will get to ask an academic geneticist about direct consumer tests and actionable advice based on them, they would tell you, there’s basically nothing that you can do with your 23andMe, for example.
Dr. Hedberg: Right, right. I do wanna mention your paper for those interested. The title is “Using Synthetic Datasets to Bridge the Gap Between the Promise and Reality of Basing Health-Related Decisions on Common Single Nucleotide Polymorphisms.” It‘s a great paper. It is freely available, and I’ll link to that so everyone can read it. Let’s just talk a little bit about how these things are actually studied. So, when we’re looking at design risk in genetics. What are the problems with the methodology in these studies from your point of view?
Dr. Wood: So, the main… Well, there’s two ways that you might look at the heritability of a certain phenotype. So, say obesity or an increase in BMI is perhaps one of the ones that was first looked at. And you can do twin and family studies which tried to sort of isolate the effect of genetics like what is passed down from parents to children, the difficult to control for the effects of a shared environment. But sort of looking at population in general, you might do something called a genome-wide association study where you look at hopefully hundreds of thousands of people and then maybe millions of potential SNPs and you look at which particular SNPs might then be associated with a given phenotype. So, say an increased risk of obesity or an elevated average BMI. And then from there, you sort of can dig in a bit further and try and quantify the effect.
There is a problem with doing that because you’re looking at more SNPs than you have people to study. And for statistical reasons, this basically means that you’re likely to overestimate the effect size of a given SNP. So, that’s one aspect, but then when you try and quantify the effect and then report it back, so you might want to tell somebody that there’s a given effect size of say, an FTO SNP, so the Fat and Obesity Associated protein. There is one SNP in the FTO gene that’s probably the single SNP that’s most associated with an increase in BMI or risk of obesity. And they might say, on average, if you have one copy, your BMI is 0.3 higher, which is about 2 pounds in body weight for an average person. And then it’s double that if you have two copies of this. So, you can have either one, two or zero copies of any given SNP.
The problem there is that those are based on singular averages. So, you take the mean, you know, you add up all the BMIs and everybody with a given genotype and you divide that by the number of people and then you do the same for those with a SNP. And then just on average, you might see a slight increase. The real problem comes from the fact that there is so much variability, which is lost when you try and describe that average increase. So, the thing that I did in the paper was using basic statistical theory. If somebody tells you the mean and standard deviation of, say, BMI for a given SNP, you can then reconstruct a full data set that follows a Gaussian or normal distribution, which it should. And then you can look at, say, how much does the full distribution of BMI is in those with a higher risk genotype overlap with those with a lower risk genotype.
And you can do that for any single genotype. You could do it with polygenic risk scores as, you know, multiple SNPs affect the same disease or disease risk. And what you start to see or what we saw is that for most single SNPs that people are talking about in terms of disease risk, there is more than 90% overlap between the high risk and the low-risk genotypes. So, that means that if you have, say, two copies of the higher risk FTO SNP, you still…90% of the people with that genotype would have a BMI that is perfectly in keeping with a low-risk genotype. So, then only 10% of people might have a BMI that is associated with an increased risk due to genotype. And so that’s a very different way of talking about risk. So, if somebody just talks about the average effects, they might say, “Oh, you’re going to be on average four pounds heavier.” Whereas in reality, there are probably less than 10% of people who will see any effect on their weight because of their genotype. And when you look at the effect of the genotype on BMI in total, FTO genotype explains things about 0.2% of the variability in BMI. It’s so tiny that is basically inconsequential.
Dr. Hedberg: Yeah, that was so interesting about your paper. I mean, some of these numbers for some of the SNPs that you mentioned, you know, the overall, the actual impact on the individual was sometimes less than 1%, you know, 0.4%, 0.09 to 0.05%. And that alone is not factoring in all of the factors in an individual’s life on top of that. I mean, we don’t know if they were breastfed or, you know, fed formula or if they had a lot of antibiotics the first three years of life. We don’t know they’re necessarily, you know, smoking, exercise, adverse childhood experiences. I mean, there’s so many factors that could come into play in these numbers. Do you agree with that or do you think that there’s been a good job of taking into account all of those confounding factors.
Dr. Wood: So, in the studies, you know, as they do them, you know, these genome-wide association studies and similarly with the Mendelian randomization studies to look at the effect of, say, a wide range of LDL cholesterol levels or homocysteine levels on disease risk. The baseline assumption is that if you look at a large enough group of people, then the effects of those exposures kind of disappear. And so they don’t account for them because they assume that they have a large enough group size, it shouldn’t be a problem. And to some extent, that is true. And when you look at, you know, the real totality of the data that exists on SNPs and their effect on any given disease risk, in reality, almost all of it is driven by the environment. And so those are all the things that you mentioned.
And in particular, when you’re looking at some of these SNPs, so, again, obesity-types diabetes, you know, these are diseases that are very common in industrialized societies. And if you look at, say, a polygenic risk score, so you take all of the SNPs associated with obesity, and the most recent paper, I think you use 141 total SNPs to create a polygenic risk score. But even those in the lowest risk genetic group, which is actually relatively rare, their BMI was over 25. So, on average, even the lowest risk genetic group, these people are overweight. And what I think that really tells you is that if there is an effect of these SNPs, which overall is very small, so, in that paper, they said that 141 SNPs predicted or was associated with 13% in the variation in BMI saying that 87% is directly driven by, you know, other factors in the environment. But you can only say that this is the case even that 13% in a population that is, you know, a baseline overweight or obese and in the setting of a modern westernized environment. So, once you take those factors away, if you’re working with a patient or you yourself are removing some of these factors or, you know, changing your environment such that you don’t have the same obesogenic environment as the average industrialized population does, these SNPs become even less important.
Dr. Hedberg: Interesting. Yeah, that’s why I wanted to have you on because your knowledge of statistics is exceptional in really understanding this. So, we talked a little bit about obesity and just the psychology in this is just really interesting because people who… Some people just say, “Yeah, I’ve got the fat gene. There’s not much I can do about it.” But it just appears that that has very little impact on the individual’s ability to maintain a normal BMI. And when I was doing graduate-level courses in molecular genetics, my genetics professor, he kind of explained these, you know, the way to explain it to laypeople is that these SNPs are what genes are like an audio dial, you know, I wanna say a scale of 1 to 10 and they can be turned up to a 10 or turn down to a 1 based on all the factors in the individual’s life, sleep, exercise, stress, nutrition, etc. And I thought that it was kind of an interesting way of explaining it and that’s something that I think a lot of people don’t understand. They think that if they have the SNP, then it’s just 100% active all the time and there’s nothing they can do about it for the rest of their life. What do you think about that way of looking at it?
Dr. Wood: Yeah. I think this deterministic view of genetics really has or should have died out as we learned more and more about the genome, the epigenome, sort of the interactions that occur there. And when you look at certain SNPs or certain genes based on, you know, maybe multiple SNPs, you might have a range of different functions. But that tells you about the function… So, say SNP or a gene encodes for a protein, it’s an enzyme. And based on SNPs, that enzyme function might increase or decrease. Absolutely, it can be… It’s probably… It’s unlikely that it’s gonna go all the way down to a zero on the volume scale, but maybe it’s gonna be somewhere between, you know, 3 and 10, so, like, 30 to 70% or 30 to 100%, something like that. And so if you measure the activity of that enzyme in a test tube, you’ll see that there’s an effect there, right? It’s a less active enzyme. But when you think about what a gene does and how it fits into sort of the systems within a body, so you have the activity of the enzyme itself, but then it does something, right? So, it has a substrate and a product. And some things will be required to make the substrate and some things will… And the product will maybe do something as well. And those are going to feedback and tell the cell, “Do I need to make more or less of this protein?” And there are gonna be all these other factors like circadian rhythm is gonna change transcription factors, which is gonna change the level of the protein, and maybe you’re gonna need some co-factors or some vitamins or nutrients for that system to function.
So, say that I have a combination of SNPs that reduces the function of one of my enzymes by 50%, because of a combination of all these other things, maybe I just make twice as much enzyme and then I have essentially 100% function or, you know, maybe all those other factors come into play and, you know, if I make sure that I maintain a robust circadian rhythm and I have a good, you know, nutrient status by just eating, you know, a wide range of nutrient-dense foods, none of this matters anymore. So, people talk about, you know, X% function of a gene, but that’s… Even for that pathway, that gene has a very small part to play in terms of all the other things, you know, the amount that gene is transcribed, the number of proteins made, all the different co-factors substrates things that are gonna feed into that system. And in reality, you know, maybe some balance is found that means that there’s really no overall meaningful change in function of the system. And I think that’s really what’s happening. Most people have some slight changes in function of genes and proteins, but the same overall balance is maintained as long as, you know, the necessary inputs are there.
Dr. Hedberg: Let’s get into some specific SNPs. Let’s cover the elephant in the room first, which is the MTHFR. This has definitely been the most frustrating for me as a practitioner talking to patients about MTHFR because a lot of them will come in believing that it’s a serious part of their illness, it’s having a major impact and a cause of their disease and their symptoms, and everything there that they’re going through. And part of that is because of what they read online and what people are talking about and forums and groups. And then you’ll hear claims of, “Well, nothing really worked for me until I just took a lot of methylated folate.” And one of the things people need to understand is that there’s… I mean, studies show there’s anywhere from about a 40 to a 90% chance of a placebo effect if you believe something is going to work for you. And so that’s the first thing that comes into play. And then the other aspect is practitioners claiming that it’s very important. And every time I asked them, “Well, what else did you do with the patient? Did the patient just come in and you gave them methylated folate and that was it?” And that’s never the case. It’s always big changes to the diet, exercise, other supplements, so many different interventions going on, and so how can you single out an intervention like that as the cause of the patient getting better? So, what is your overall take on MTHFR and what the research shows? And is it actually something that we should worry about or is it something we should just put aside?
Dr. Wood: Yeah, the MTHFR. Obviously, if you’ve sort of spent time in the functional medicine arena, you’re right, it’s the elephant in the room. And it’s also a nice case study because, like I intermated before, there are two SNPs that are most commonly talked about in the MTHFR gene, A1298C and C677T. And you can have, you know, one or two copies of either and they interact to create different levels of gene function. So, you can look at a phenotype based on the percent function of the enzyme, which is really nice. It’s sort of you… There’s a range. And so it’s worth first saying that more than 85% of people have at least one of those SNPs that results in less than 100% gene function. Right? So, the vast majority of people have, as I’ve heard, you know, quite, you know, smart people say they have an MTHFR gene that doesn’t work properly, right? That’s the language that immediately is brought forward when you start talking about this, which, you know, if that’s the standard, then obviously that’s not true even to begin with. So, I found this interesting for me because I have one copy of each SNP, which means that I have more than 50% loss of the function of my MTHFR protein if we look at it in a test gene like I talked about it.
So, one of the ways that you can look at MTHFR function in terms of a phenotype is homocysteine level. And that’s not perfect, right? There are multiple escape pathways for homocysteine. It’s not just affected by MTHFR function. However, there are plenty of studies that look at MTHFR genotype and homocysteine. So, you can look at what effect your SNP or SNPs might have on your homocysteine level. And so, I did this in a similar way, and it’s in the paper. People can go and take a look at it. And what you see is, first of all, that the effect isn’t linear, which is what most people assume when they’re saying, you know, you have X% reduction in function, so you need X% more choline or methyl folate.
So, firstly, that’s not true. And secondly, if you look across the range of the most common MTHFR SNPs and combinations, your MTHFR genotype basically explains about 8% in the variability in homocysteine which is just a tiny amount considering, like, how much people say, you know, how important MTHFR is for function of this system. And in reality, all these… So, many other things are gonna come into play. And when you look at one specific outcome like homocysteine, MTHFR is basically meaningless in terms of what your homocysteine level is. And I find it really interesting because when I speak to people about this, there’s so much pushback because they are certain that MTHFR is important. I remember speaking to one who is a coach who was saying that for them, you know, knowing about MTHFR was really important because it meant that they found out that their homocysteine level was elevated and they did something… I think they improve their diet slightly, maybe a bit more choline. And then, you know, things improved. But I would, you know, ask, what does knowledge about the MTHFR gene assist with that? If you just measured your phenotype, if you just measured your homocysteine level, what does knowing about MTHFR do to improve your ability to act on that? And in reality, there isn’t any, but people have sort of attached this level of importance.
So, when you look at MTHFR and various outcomes, the research is incredibly mixed. Sometimes it’s positive, sometimes it’s negative. If you really dig into the details, I’d say that most of the time, it doesn’t really have any effect, but it’s hard for people to hear. And that’s the one where I’ve gotten the most pushback despite the fact that, you know, if you find the papers that you think say MTHFR is associated with a given outcome, in my paper, all the tools that you can use to prove me wrong, and I’m very happy for you to do that. There’s nothing hidden there. You can use freely online available tools. You can dig into that yourself and I obviously can’t know or at least I can’t know all the papers. But I want people to better understand how they can look at this themselves. And based on what I’ve seen, I don’t think MTHFR is really anything to worry about for most people as long as they have an adequate nutrient status, a decent diet, and minimize exposure to, you know, various environmental toxins and all that, the exercise and all that kind of stuff in which I would say that for anybody regardless of their genotypes.
Dr. Hedberg: Exactly. And I do explain that to patients. This is just not really important. And it was my understanding about MTHFR just looking at the whole biochemistry of it was if you had… If you have adequate B12, folate, and, you know, some adequate choline in your diet and some, of course, riboflavin, I mean, that’s kind of it as far as the building blocks to just make sure everything’s working well in that pathway. Do you have anything to add to that?
Dr. Wood: No, I think that’s it, really. And the riboflavin is a great point because these SNPs, they basically affect the ability of the MTHFR enzyme to bind to FADH2, which is made from riboflavin. And there’s some nice studies showing that particularly with those who are homozygous for the 677T, those guys have about 75% reduction in their enzyme function and a much greater variability in their homocysteine levels compared to everybody else. So, that’s why the effect isn’t linear. But if you give those guys just a tiny amount of riboflavin, and I think the study gave them 1.6 milligrams, then that significantly reduces the homocysteine levels. So, if a nutrient replete, and again, probably would just require you to eat, you know, occasionally a few eggs and some liver or maybe some meat or fish. That’s gonna do most of the job. And I don’t think you need to really worry about it beyond there.
Dr. Hedberg: Yeah, agreed. I did do a deep dive into MTHFR. I think it was last year. I wasn’t able to find any evidence that doing any kind of specific intervention really does anything as far as symptoms or reducing disease risk. In fact, the geneticists that I read their statements basically echo that there’s no evidence that treating, you know, MTHFR really does anything. So, did you find that as well?
Dr. Wood: Yeah. So, in line with that, I put my own 23andMe data into an online choline calculator, which was supposed to tell me how much extra choline I should eat based on my MTHFR function. And one of the paper… And so the main paper that the recommendations were based on. So, basically, overall I have 50% loss in function, so I should eat twice as much choline as somebody who had 100% function was kind of what the calculator said. But the paper that was referenced was a paper where they gave extra choline to 13 folate-deficient Mexican-American men. So, it’s a tiny sample size. We know that ethnicity and race play a huge role in whether SNPs are penetrant or not. And there was the confounder that this group was already folate deficient. And then they looked at methylation function or like total methylation. And even despite giving them extra choline, there was actually no difference in methylation, but then this was the paper that was being used to recommend that I eat twice as much choline. So, just so many parts of that make no sense whatsoever. And like you said, when you look at various interventions, none of them show a significant effect one way or the other in people with varying levels of MTHFR function.
Dr. Hedberg: Yeah. It’s difficult to navigate this industry because there’s so many papers that you have to read to understand everything and fact-check everything. And I understand why not every practitioner is doing that or has the time to do that. I mean, you almost need a research team to investigate every single thing that you’re doing. And everybody does the best that they can. But it’s interesting you brought that up about the study was done on people with a folate deficiency, and you can let me know if you agree with this or not, but almost all of the papers that I read on micronutrients, you always get great results when the participants are deficient in that particular nutrient, but not if there’s sufficiency. So, there’s no… There are rarely any studies that I’m aware of where if the patient has sufficient levels of a micronutrient that their body needs, excess amounts don’t necessarily give you exceptional outcomes. Would you agree with that or are there any cases where you might disagree?
Dr. Wood: No. Absolutely. I think that’s… There’s obviously a baseline level that we require. And I think for many nutrients, probably the majority of people eating a westernized diet will be deficient or at least insufficient in those, and if you supplement with them, you will see benefits. However, like you say, I think particularly people listening to this podcast, they are patients, you know, if you’re recommending a nutrient-dense diet and maybe you do some… I would do some, you know, phenotype testing, right? You test for a level of a given nutrient ideally in the blood because we understand those much better than some of the other tests. And if somebody is deficient or insufficient, you replace that. You’ll see benefit. But beyond that, you know, you almost never see benefit. And in some cases, you may actually cause harm by, you know, adding loads of some particular variant of a nutrient to a system that doesn’t need it.
Dr. Hedberg: Right. Right. Let’s jump into the second big SNP that’s talked about… At least this is the one that I tend to come in contact with the most with patients and practitioners is COMT. And this is the… The idea is that you’re either a worrier or a warrior depending on your COMT gene. So, can you explain that and what the actual impact is of having COMT if there is any impact?
Dr. Wood: Yeah, absolutely. This one, again, you know, when you sort of look at this yourself, you can always find an interesting story that you want to better understand. So, with the COMT gene, there is SNP that causes a change in amino acid in catechol-O-methyltransferase. And if you have two copies of the methionine SNP, then you have faster, supposedly a faster COMT activity. This means that you break down dopamine much faster. So, you have less dopamine in your prefrontal cortex. This makes you better or more resilient to stress, but you have a lower IQ and lower executive function. So, that’s me. So, if you’re listening to me talk about this stuff, remember that I have a low IQ and poor executive function, so you’re probably not worth listening to anything I say. Conversely, if you have two copies of the valine version, then you have slower activity, more dopamine, supposedly, that means you have more likely to be anxious, but you have a higher IQ and higher executive function. And this is sort of what is generally said about those SNPs. And so what you might actually be interested in is we probably don’t really care how much dopamine is in your prefrontal cortex. You might care about cognitive function, let’s say.
So, if you look at the largest studies, looking at COMT SNPs and their effects on various metrics of cognitive function, you know, the big ones where you’re looking at several hundred people basically say, “There’s no difference. It doesn’t make any difference.” And so, if you really dig down, so I looked through all the tests, so I did find one study, they looked at 500 people and they found that those who were the worrier type, that had faster COMT activity, they perform slightly less well in a version of the number-letter test, which is where you give people a collection of numbers and letters and then they have to recite them back in alphabetical and numerical order. And then, so I did like an analysis on this data and about 4% of the variability in performance in the test was explained by COMT. So, again, you know, more than 95% due to everything else that plays into cognitive function.
But when you really dig into this, and this is one of sort of my favorite personal stories as I was digging into genetics. I was looking at, “How do we know about COMT SNPs and how they affect the gene function?” And there’s one original paper which everybody cites back to, and they took the brains of cadavers and they looked at their genotype, and then they extracted COMT from the brain and then they looked at its activity in a test tube. And those who had the warrior genotype had, on average, 38% greater activity than the worriers. But interestingly, if you then try and reconstruct a full data set that sort of describes the full variability like I’ve done in the paper for the field SNPs as well, what you see is that actually, the data that they present is inaccurate in the paper because they don’t tell you what the error bars are. They just give you a graph and then an error bar. They don’t tell you what the error bar is. But if you sort of like by, you know, sort of deduction, you can figure out that the way they describe the data set is inaccurate because they’re assuming that it’s normally distributed when it isn’t and there’s vast variability. If you try and reconstruct the data set, the random number generator that I use wants there to be negative numbers, which is impossible to make the data fit the way it’s described in the paper.
And this makes perfect sense if you try and understand…well, if you do understand how these studies are done. So, you have to take cadavers, and there’s gonna be a certain amount of time before you get access to the tissues and a set amount of time for you to process it, look at it. All of that is gonna result in huge variability in the data. And that’s just to be expected if you do those kinds of studies. So, the original study that everybody cites, back to say that this SNP is associated with X% change in function of COMT, basically, because of the way the study was done, you can’t really trust the data. And so like… But nobody really thinks about that. So, even like, if I tell you that there’s a 38% difference in function, that’s probably not even true. But that’s, again, you know, these myths propagated forwards because it sort of helps us tell a story, but A, the original data probably isn’t trustworthy, and B, if you then do look at SNPs and cognitive function, they don’t really make any difference.
Dr. Hedberg: Exactly. And I have patients who believe that this is the single cause of their depression or the anxiety or their mental illness. And that alone, as we talked about earlier, is enough to affect the biochemistry.
Dr. Wood: Absolutely.
Dr. Hedberg: And that kind of ties in with the CREB1, which I just wanna have us talk about a couple of these athletic type SNPs. So, CREB1, the endurance gene. And what was interesting about this that you wrote is that if you think you don’t have the endurance gene, this actually affects your performance regardless of the actual genotypes. Can you talk about CREB1 endurance?
Dr. Wood: Yeah. This is a brilliant paper that came out in “Nature of Human Behavior” in 2019. And they took people and they made them do a treadmill test. And so they looked at their performance on some, like, a standardized test. And then they took their… They measured the genotype of this gene, CREB1, which is associated with improved aerobic performance. And then they told the participants either that they had the good version of the gene so that, you know, they were gonna have a good version of the aerobic gene or that they had the bad version, right? So, two copies of the bad version of the aerobic gene. And then they retested them and they found that those who were told they had the good version did about the same as they did on the first test, treadmill test. Those who were told they had the bad version did worse.
So, being told that they weren’t genetically good at aerobic endurance made them perform less well. And there are, you know, just dramatically increasing number of examples of this, you know, being told that there’s something about your physiology is gonna have a much bigger effect. Thinking that you’re gonna have an effect is much bigger than the effect itself. So, those effects on people’s performance happened regardless of what their actual genotype was. And in the same paper, they told people about their FTO SNPs, so again, the obesity risk. And then they did standard meals and looked at their satiety. And if they were told that they had the high risk or the low risk genotype, that actually changed their hormone levels, their GLP1 and their…which is one of the increase in the gut associated with, you know, satiety signaling, and their actual, you know, feelings of satiety after the same meal. So, being told that you have a certain genotype regardless of the genotype that you actually have, it changes hormonal signaling, it changes levels of hormones associated with that process.
And you’ll see this again and again. And I’m just bringing this up. It’s a tangent, but just because I was reading these the other day. There were two recent studies that looked at sleep trackers, and they randomized people to tell them whether they had good or poor sleep the night before. And regardless of how they actually slept, those who were told that they had poor sleep, performed less well in cognitive tests and felt sleepier during the day even though it had nothing to do with how well they actually slept. So, there are all these things that you do in the sort of functional medicine space that if they don’t…that you actually have a much bigger effect based on what you tell the patient rather than what is actually going on, either their genetics or poor-quality sleep tracking. You can have a… And you’re much more likely to have a negative effect than have a positive effect. Like with the endurance gene to being told that you have a good gene makes you perform just as well. Right? So, you can never get better. You just get worse based on what people are telling you, based on genetics.
So, there’s a huge amount of harm that you can do when you talk about that your gene isn’t working properly. This is the language that’s used around MTHFR. And similarly, I was watching a video somebody sent me on obesity the other day and there was a doctor saying that 70% of struggling with obesity is genetic. And that’s incredibly disempowering. You’re basically telling somebody that there’s nothing they can do about it because it’s all in their genes, which, you know, even if there is an effect of the genes, it’s all driven by the environment which you do have control over, right? There’s a huge amount that you can empower yourself with if you look at it from the right direction, but that’s not what most people are doing.
Dr. Hedberg: My listeners know that I have a deep interest in psycho-neuro immunology, and so this doesn’t necessarily surprise me actually because I can bring up a few examples. And, for example, the pain literature. If a doctor and authority figure, you know, shows you an MRI or an X-ray and says, “You have this. You’re gonna have it, you know, for the rest of your life.” That actually has a significant impact on the patient’s pain level going forward, just being told that they have a problem and they see it on the film, and they’re told that by an authority figure. And then people were given two tubes of cream and I had the exact same cream in it but one tube was labeled the hot cream and the other one was labeled a cold cream, and they all reported feeling, you know, a burning or a hot feeling from the one labeled hot even though it was the exact same as the cold, and the people that had the cold tube said that they actually felt cold from the cream even though the cream had no impact on temperature. There’s just so many studies like that about what we believe affects our biochemistry from allergies to mental health and then these things that you’re talking about with endurance. So, it’s just a really fascinating field to look into. ACTN3 is the other kind of athletic SNP to talk about. Is there anything you wanna talk about ACTN3?
Dr. Wood: Yeah, absolutely. So, there are… I mean, at this point, there are dozens of SNPs that people talk about in terms of, say, response to exercise or trainability and then use it to try and give you some… Just like people are using SNPs to tell you how to eat which certainly isn’t evidence-based, they’re doing the same thing for training. And this, again, you know, I have a story behind this because… Like you mentioned in the beginning, I work with some Formula One drivers and it’s very popular or, you know, if you have some kind of device or test or something and you can get it in the hands of a Formula One driver, it’s great for your marketing, right? These are, by various metrics, the best motorsports drivers in the world and they’re only ever 20 of them at a time. So, these are very rare individuals in terms of being able to work with them. And it’s great if you can say, “Oh, yeah, so and so person is a Formula One driver. Use my test or use my device or whatever.”
So, I was sent the results by the coach of one of the drivers of a genetic training tests. So, they tested this guy’s genetics and they gave him a report. And one of the things that came up was, you know, they looked at three or four genes on muscle fiber type. And one, he had two copies of this SNP and the ACTN or the actinin-alpha-3 gene. And in his report, this is like a big red light, is like this is bad. And then it says, “The proportion of fast fiber is lower than the general population, which, of course, you’d have a lower response to strength training. Now, bear in mind, this is one, like, the fittest people, you know, A, in motorsports but also compared to the general population just incredibly fit, you know, top point something something percent.
And so to begin with, that doesn’t make any sense. But then, you know, there’s no references attached to that. But what really bothers me is in line with other things that we talked about is that you’re telling an elite athlete that their training isn’t gonna work for them. So, you’re telling them that they’re not gonna respond as well to training which is then going to affect their performance, right? And their performance involves driving at a concrete wall at 200 miles an hour. And as soon as you start trying to introduce non-evidence-based thoughts into that process, you know, I do have a big problem with that. And when you look at their statements, there’s no references, of course, anywhere in the report. So, then I’ll go and dig into this and look and see what I can find. And there’s one main study that looked at ACTN genotype and response to training. And it had and I think it was about 60 people, half men, half women. And they did see a statistical trend in terms of response to training and like a peak power change after a chunk of training. So, it wasn’t significant, but there was a statistical trend between those who had two copies of the good version and two copies of the bad version.
But this was in a group of older men and women over 65 training 3 times a week, doing 4 to 5 sets of 10 leg extensions, which is just not relevant at all to the athlete who is being told that they’re not gonna respond to strength training, you know, this elite athlete. And there’s no studies in a population that might be relevant to him. And again, if I… So, I use this data even though it isn’t great. I try and do the same thing. And then your ACTN genotype may explain, you know, 5 or 6% of your response to training. So, again, it’s just this tiny fraction compared to all these other things, which actually even in Formula One driver, all the other lifestyle environment factors are gonna play a much bigger role because these guys are in a different time zone every week, traveling continuously, very high stress. So, there are all these other things that are gonna be so much more important. So, not only have you negatively affected some of the cognitive aspects of the training, you know, also… Everything else is gonna be so much more important.
Dr. Hedberg: And I know people who are tailoring their entire exercise routine around these once they find out. So, I’ve known people who quit running and just changed to running sprints based on this and also completely changing their rep scheme and, you know, the amount of weight they’re lifting and things like that if there were fast-twitch versus slow-twitch.
Dr. Wood: So, there was one study that came out sponsored by a company called DNAfit in the UK. It came out a few years ago now, that randomized people based on their genetics to a different training methodology based on whether they were largely endurance or strength type and then they looked at their… But it was both training type or both training programs were sort of resistance-based and then they looked at various different performance metrics and muscle gain. And for those who had like a synchronous like their genotype and the training program they were randomized to, lined up seemed to do the best. However, I mean, you think, “Wow, that’s really important. This is gonna be something that we’re gonna see a lot more of.” Nobody has been able to reproduce those results. Like, there is no other study that randomizes people to training methodologies based on their genetics, and then they see benefit from tailoring based on genetics. So, there was this one paper that made me super-excited about this as a possibility, you know, back when I also had more faith in SNP testing as a personalization method, anyway, but it just hasn’t… Nobody’s been able to do the same or nobody hasn’t published anything similar. So, there’s really, again, no evidence to support that approach.
Dr. Hedberg: And the same thing with eating correct, so the fat versus the carb genotype. Can you talk a little bit about that?
Dr. Wood: Yeah, yeah. There’s a number of SNPs that are supposedly associated with, you know, better responses to low carb versus high carb diets. And actually, right at the beginning of me getting into all this, that was what started. I heard a very well-known functional medicine practitioner say… I think they said, “I’m a low-carb genotype, but my partner is a high-carb genotype,” or something like that and immediately, I was like, “Okay. There’s something I need to dig into here.”
And when you look at the data that exists, again, so you have these genome-wide association studies, and not only that the genome-wide association studies flawed in their own ways that we talked about earlier. It doesn’t mean that they shouldn’t be done, but it just means that there’s some caveats to that. And then you introduce another factor, which is nutritional epidemiology, which is basically nonsense most of the time because you just don’t know what people are eating despite what they tell you that they’re eating. And then you sort of intermix those and out pops some genes that are supposedly gonna be better, you know, tell you whether you should eat low carb or low fat. And there are no interventional trials that show that there is a meaningful effect there. And I think the best one that’s been done to date was the DIETFITS trial that people may have heard of. Christopher Gardner is sort of a very well-known researcher in that space. And they randomized people to either low carb or low-fat diets based on whole foods in general so they dramatically improve food quality. And then after, like, a certain amount of restriction, then people were told, “Find a level of carb or fat intake that sort of is sustainable for you.” And what… And then they did a post-hoc analysis or like a secondary analysis of the results. So, the initial results said that it doesn’t matter if you go low carb or low fat. If you improve diet quality and find something sustainable, then weight loss is the same.
And then they looked at people’s genetics and they separated people into being a low-carb genotype, a low-fat genotype or, you know, there was like a mixture of the two where there wasn’t really a clear signal one way or the other. And regardless of genotype and regardless of which diet you were randomized to, everybody lost the same amount of weight. So, there’s really nothing, again, that says, “Oh, yes, you’re somebody who should be eating more carbs or you’re somebody who should be eating more fat based on your genes.”
Dr. Hedberg: Yeah. Exactly. And there’s two more SNPs I just wanted to squeeze in. You and I had exchanged some emails this past week about these. So, the VDR, the vitamin D receptor. The current understanding among a lot of practitioners is that if you have the vitamin D receptor polymorphism that you’re at an increased risk of autoimmune disease. And what did you find in your analysis of that?
Dr. Wood: Yeah. I spent some time looking at this yesterday, in fact. And there were four VDR SNPs that I sort of talked about, Fok, Bsm, Apa, and Taq. And unlike most other SNPs, these are actually named based on bacterial restriction enzyme cleavage sites. So, this is kind of like the old, old school method of trying to figure out types of genotyping, which people may have learned if they learned biochemistry in college. And so these are the four they’ve looked at in terms of association with autoimmune disease and Hashimoto’s thyroiditis, you know, particular probably, you know, because it’s common. People are very interested in the intersection with vitamin D metabolism.
So, looking at three meta-analyses. So, again, not just looking at a single study. Looking at multiple populations, multiple different data sets. So, one meta-analysis I found said that Taq was associated with a decreased risk in Asian and African populations. Bsm was associated with a decreased risk in African and European populations, but an increased risk in Asian populations. And Apa was associated with an increased risk in African populations. So, that’s one, you know, sort of like increase, decrease risk, ethnicity and race certainly seem to play a role. But then the next meta-analysis says, “Well, there’s an increased risk with Bsm and Taq, but not with Apa and Fok.” And then the next meta-analysis says, “Well, Fok is associated with an increased risk in Asians but not any other population, and there’s no effect of the other ones.” So, if you’re gonna do a meta-meta-analysis, in reality, there’s no overall discernible effect here. And this is… The more you look at these various studies, certainly, you might be able to find in effect in a certain population and maybe that becomes important, you know, depending on the patient in front of you. But overall, I would say that there’s no discernible, like, meaningful effect of any of these SNPs on risk of, say, Hashimoto’s.
Dr. Hedberg: Excellent. And then the last one is the glutathione S-transferase. So, the claim by some practitioners is that if they have this GST SNP, they will have difficulty producing glutathione if they supplement with N-acetylcysteine or something like cordyceps. And, again, just kind of anecdotal reports from practitioners, you know, practices and things like that. But do you find anything that substantiates that claim that someone should just take glutathione on its own if they have the SNP as opposed to say NAC?
Dr. Wood: So, I think it’s an interesting claim to make because GST isn’t involved in the synthesis of glutathione. It’s involved in the use of glutathione. So, it’s the conjugation of glutathione to a molecule that contains a free radical. There are two main GST SNPs that people are probably talking about, there’s the M1 and the T1 null mutation that you might read about. And they are associated with a decreased level and function of the GST enzyme. And depending on the study, may increase your risk of certain cancers or if you smoke, it may increase your risk of COPD, probably just because you’re not quite as good at falling into the trap of telling you you’re not gonna be good at this because of the function of the enzyme you might not be able to clear as much of the oxidative radicals, but we’ll address that again at the end. It’s worth saying these are very, very common SNPs. So, more than 50% of all the GST levels in European populations are M1 null. So, that means that more than 50% of people have, or around 50% of people have one copy and 25% of people on average will have two copies. In East Asian populations, nearly 50% are T1 null. Both are very common depending on the country. In African populations, you might have 20 to 50% of each in different ratios. So, again, probably the majority of people are gonna have at least one copy of one of these SNPs.
So, when you then look at studies of whether people with these GST SNPs respond to NAC, which is the specific question. Actually, you find almost the opposite. So, NAC does seem to reduce the risk of mortality in people with ARDS, acute respiratory distress syndrome, they are in intensive care units. And there was another study that looked at changes in hearing based on noise exposure. And again, those with either one or two null SNP copies of the GST enzyme, they actually did better on NAC. Well, they were the ones that responded to NAC. So, there’s no evidence to suggest that if you have a GST SNP, you won’t respond to NAC. And I have not seen any evidence that glutathione is gonna be better than NAC for any important outcome. NAC is very well studied, very well understood. And so there may be a case to say, yes, people, you know, with these SNPs, which again, very common, maybe the majority of people compared to the minority of people who don’t have these SNPs. Yes, you may have an increased susceptibility toxic of stress, but, you know, the advice is gonna be the same in terms of nutrient status, minimizing exposures, maximizing the health of the antioxidant system through hormetic exposures like exercise. All of that is gonna be the same regardless of your SNP. So, yes, there may be a biochemical function, but does that change your advice? No, it doesn’t. And I think that’s the important thing.
Dr. Hedberg: Excellent. So, as I said earlier, you know, it’s difficult to navigate for practitioners because, you know, we go to functional medicine conferences and there’s a bunch of labs there that offer genetic testing. And it’s presented in a very neat and tidy model where you just run the test and then the patient is supposed to take all of these supplements to address their genes. So, I think that’s one of the reasons why it’s taking off because there’s a lot of money to be made in genetic testing and selling supplements to address the individual SNPs. And that’s a problem and I am worried about it. I’ve been worried about it for a long time and that’s why I’m so glad you were able to come on here and talk about the real science behind it. I think we’ve covered a lot today. Is there anything else you wanted to add that you really think practitioners or the layperson should know about regarding genetic SNP testing?
Dr. Wood: I think that gives a, you know, sort of, like, a nice broad overview of, you know, where the evidence really stands. I think the most important thing to me is that if people think this is important and they want to use it in their practice, like, I don’t necessarily have a problem with that, but you should understand the evidence that exists behind your recommendations. And like I said, your link to the paper, and the tools to really dig into this are there for anybody who’s willing to invest the time. And it’s important because you basically are more likely to do harm than good with the current state of the science, and I think that’s… I think most practitioners want to do good. They want to help. They want to help their patients. And the possibility of doing harm of disempowering the patient by looking at these tests and also incurring unnecessary costs for tests and supplements. I think that’s where we need to step back and say, “Is this really worth us doing?” And the vast majority of evidence suggests that your recommendations should stay the same regardless of SNPs, regardless of genotype. That’s where we really are at the moment. And maybe that will change, you know, and that’s fine, but that’s really where we are right now.
So, I think it’s just worth thinking about how communicating these things with your patients is going to affect their physiology regardless of what the SNP actually does. And so just thinking about that and really digging into the SNPs that you think they’re important, so, great. Find the papers, you know, dig into the data, you know, take into account things like ethnicity which play a big role in terms of overall phenotype based on genotype. And in general, the research is very sort of European-centric. And similarly, more than 70% of the genotypes in 23andMe’s database are taken from white people. So, when you then try and apply that information to those who are black or have other different backgrounds, you know, the data, even if there is a small effect, it becomes even less meaningful. So, taking all of those things into account, really taking the time to sort of understand I think is really important. And it’s just because it’s gonna affect the outcome of your patients, which is what I truly believe people are trying to improve.
Dr. Hedberg: Exactly. And I like what you said. You do risk doing more harm than good in some individuals. And that’s really a kind of the core tenet of practice is the last thing you wanna do is do harm, and so we have to be really careful and prudent about what we choose to do and what kind of interventions we want to use with patients. So, Dr. Wood, where would you like people to find you online?
Dr. Wood: The easiest way is probably to follow me on Instagram @drtommywood on Instagram. There’s usually… I’ll post all of my own science publications there, but then also, you know, some more general training…some training stuff because that’s something that I’m personally interested in and you’ll see pictures of my dogs pop up frequently as well. I am @DrRagnar, R-A-G-N-A-R on Twitter. Ragnar is my middle name. And I also have a website, drragnar.com, although that’s kind of fallen behind in terms of updates, so Instagram is probably the best place.
Dr. Hedberg: Excellent. Well, this has been great. Thank you again for coming on. And for all the listeners go to drhedberg.com if you want to read a full transcript of this. And we’ll have links to Dr. Wood’s paper as well as links to anything else that we talked about. Well, take care, everyone. This is Dr. Hedberg, and I will talk to you next time.