Whites have higher 25(OH)D than every other racial group, and the conventional explanation is that light skin evolved to allow sufficient vitamin D synthesis far away from the equator. In episode 24, I explain why these differences may relate to genetics of vitamin D metabolism that have nothing to do with skin color and may reflect a lower average need for 25(OH)D rather than a lower average ability to get enough. But “average” is the key word and when it comes to using this information on a practical level we need to look beyond racial categories and treat each person as an individual.
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This episode is brought to you by US Wellness Meats. I use their liverwurst as a convenient way to make a sustainable habit of eating a diversity of organ meats. They also have a milder braunschweiger and an even milder head cheese that gives you similar benefits, as well as a wide array of other meat products, all from animals raised on pasture. Head to grasslandbeef.com and enter promo code “Chris” at checkout to get a 15% discount on any order that is at least 7 pounds and is at least $75 after applying the discount but under 40 pounds (it can be 39.99 lbs, but not 40). You can use this discount code not once, but twice!
Show Notes for Episode 24
In this episode, you’ll find all of the following and more (these times refer to the podcast, and they may be different in the YouTube video):
- 0:06.37 Should I offer online nutrition classes?
- 0:09.49 This will start off sounding like it’s about racial groups, but it’s really about individuals.
- 0:10:34 Blacks in America have lower 25 (OH)D than whites.
- 0:12:52 The conventional hypothesis explains this as dark skin being poorly adapted to these latitudes.
- 0:13:17 Genetic evidence suggests light skin began evolving long after the migration from Africa.
- 0:18:39 Aggregate global 25(OH)D data do not support the conventional hypothesis.
- 0:20:05 Caucasians have higher average 25 (OH)D than non-Caucasians at every latitude; Caucasians have higher average 25 (OH)D at temperate latitudes than non-Caucasians have at equatorial latitudes.
- 0:22: 32 Blacks in America have higher bone mineral content than whites.
- 0:26:19 Calcitriol dominance favors getting calcium from our food, while PTH dominance favors getting calcium from our bones.
- 0:27:59 Genetic variation in the 1-hydoxylase can account for the difference in 25(OH)D between blacks and whites in America, but this has nothing to do with skin color or racial groups in the way we have socially defined them.
- 0:35:02 Calcium intake could influence how the genetic variation translates into 25(OH)D.
- 0:37:14 This does not affect white 25 (OH)D, and it could be related to calcium intake; ancestral calcium intake could have mediated selective pressure on the relevant genes.
- 0:38:32 Blacks in the United States have higher average calcitriol and a higher average calcitriol-to-PTH ratio than whites.
- 0:39:38 Similar differences between Inuit and Danes: lower 25(OH)D, higher calcitriol, and lower PTH; a traditional diet raises 25(OH)D, raises calcitriol further, and suppresses PTH further.
- 0:41:22 Asians have lower 25 (OH)D than whites in Hawaii.
- 0 42:44 The references ranges may in effect be applying average white requirements to drive recommendations for everyone.
- 0:43:49 The Maasai and Hadza have higher 25 (OH)D, but this may be due to higher calcium intakes, and/or higher ancestral calcium intakes that influenced their genetics.
- 0:48:24 Non-whites are probably adapted to lower 25 (OH)D than whites on average, but it is individual genetics rather than racial groups that are relevant.
- 0:52:59 25 (OH)D + calcitriol can be summed for a biological activity index.
- 0: 54:09 PTH should be in the lower half of the reference range.
- 0: 56:20 Magnesium deficiency could confound the PTH measurement, but it probably has to be extreme.
Links Related to Episode 24
Vitamin D: More Is Not Better, by Chris Kresser
Mastering Nutrition Episode 9: Balancing Calcium and Phosphorus in the Diet, and the Importance of Measuring Parathyroid Hormone (PTH)
An Ancestral Perspective on Vitamin D Status Part 1: Problems With the “Naked Ape” Hypothesis of Optimal Serum 25(OH)D
An Ancestral Perspective on Vitamin D Status Part 2: Why Low 25(OH)D Could Indicate a Deficiency of Calcium Instead of Vitamin D
The Scientific Approach of Weston Price, Part 2: Problems with Comparing Different “Racial Stocks,” with Inuit Adaptations in Vitamin D Metabolism as an Example
References Related to Episode 24
Vitamin D status and calcium metabolism in adolescent black and white girls on a range of controlled calcium intakes. [PubMed]
Global patterns of diversity and selection in human tyrosinase gene. [PubMed]
A Genetic Mechanism for Convergent Skin Lightening during Recent Human Evolution. [PubMed]
Rethinking the dispersal of Homo sapiens out of Africa. [PubMed]
Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-regression analysis. [PubMed]
Influence of Secondary Hyperparathyroidism Induced by Low Dietary Calcium, Vitamin D Deficiency, and Renal Failure on Circulating Rat PTH Molecular Forms. [PubMed]
Common variation in vitamin D pathway genes predicts circulating 25-hydroxyvitamin D Levels among African Americans. [PubMed]
Americans are not meeting current calcium recommendations. [PubMed]
Dietary Influence on Calcitropic Hormones and Adiposity in Caucasian and African American Postmenopausal Women Assessed by Structural Equation Modeling (SEM). [PubMed]
Vitamin D insufficiency in Greenlanders on a westernized fare: ethnic differences in calcitropic hormones between Greenlanders and Danes. [PubMed]
Low vitamin D status despite abundant sun exposure. [PubMed]
Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. [PubMed]
Determinants of parathyroid hormone response to vitamin D supplementation: a systematic review and meta-analysis of randomised controlled trials. [PubMed]
Transcript of Episode 24
This transcript was generously provided by Cassandra Barns.
This is Chris Masterjohn, and you’re listening to episode 24 of Mastering Nutrition, where I will be talking about the evolution of diverse vitamin D requirements.
This episode is brought to you by US Wellness Meats. I discovered this company at Paleo f(X) this spring and I fell in love with them as soon as I tried their liverwurst. For years I’ve known that I feel best when I eat a diversity of organ meats like liver and heart. I have a clearer mind, feel more energetic, and my energy is much more stable between meals. But it is so hard and so time-consuming to make a sustainable habit out of preparing and cooking organ meats. US Wellness liverwurst is 15% heart, 15% kidney, 20% liver, with the remainder grass-fed beef. That’s a whopping half organ meat. It takes zero time to prepare, tastes great and finally makes consuming a diversity of organ meats a habit that I can easily sustain. But just because I’m obsessed with their liverwurst doesn’t mean it’ll turn out to be your favorite. US Wellness makes an even milder braunschweiger that’s 35% liver, 65% beef. And if you have a really sensitive palate and just want to get your feet wet with organ meats, their head cheese delivers the mildest taste with 15% heart, 15% tongue, no liver, and the remainder beef. They also sell an incredible array of other meat products in practically any cut you could want, all from animals raised on pasture. Now, this isn’t just about high-quality grass-fed meat products that can up your nutritional game and save you time in the morning. It’s also about saving money, and that’s because I worked out a special deal for you. As a member of my audience, you can go to grasslandbeef.com and order whatever you want, and as long as your total order is at least 7 pounds and, after applying the discount is at least $75, and as long as it’s under 40 pounds, you just enter the promo code CHRIS at checkout. Putting my name in the box earns you 15% off your order, and since you can order up to 39.9999 pounds of meat at that discount, you can potentially save a lot of money. If you’re on the fence or not ready for a big order, don’t worry. You can use the promo code CHRIS not once, but twice. So, order the minimum your first time, and if you love this stuff as much as I do, order the max the second time around and get the same level of discount. Or just max out your order both times and get just shy of 80 pounds of meat at the discounted price. Either way, head over to grasslandbeef.com and make sure you enter CHRIS at checkout to get the discount.
Welcome back everyone to Mastering Nutrition. Today we are going to be talking about the evolution of diverse vitamin D requirements. And by that I mean not only that different people – different individuals have different needs for vitamin D from the sun or from the diet, but I also mean that different people have different needs for 25(OH)D circulating in their blood. And 25(OH)D is the marker of nutritional status that all of us who get our vitamin D status tested actually get tested. So, you know, we have our blood drawn, we look at the 25(OH)D concentration, and then we make a decision about whether we need to supplement or not. And I’m gonna argue that that is too simplistic.
Now, I have talked about some of these concepts before, certainly. And AHS 13, that’s the 2013 Ancestral Health Symposium, is one of the places where a lot of the concepts and a lot of the data that I’m going over did get shared. However, that was the one year where the AHS videos – there was an AV problem and they did not make it onto the internet. I gave almost this exact talk in San Francisco earlier this year and in Brooklyn a couple weeks ago, but neither of those were recorded, and so they’re not available to everyone. The closest that I’ve gotten to distributing some of this content on the internet is over at Western A. Price site a couple years ago. I started but never finished a blog series called “An Ancestral Perspective on 25(OH)D”. The content does somewhat overlap with that, and so I will post links to that in the show notes. The show notes will be available at ChrisMasterjohnPhD.com/24. For those of you who prefer visual learning, I will make a YouTube video and that will be embedded in the show notes, again at ChrisMasterjohnPhD.com/24. I do want to give a shout out to Chris Kresser. Chris and I have been communicating about these concepts behind the scenes. He’s been incorporating these principles into his own clinician training program, which I’m really excited about. But he also kind of took some of these principles and expanded on them into other research that he’s been doing on vitamin D, and practical take-home points that he put into an article “Vitamin D: More Is Not Better”, so I will link to that in the show notes as well.
What I want to do here is not only discuss the practical points of what we can do with this information, but I also want to flesh out the perspective, and try to understand why is it that we should view vitamin D this way, and why might it be from an evolutionary perspective that – and, you know, some of this will be speculative, but why might it be that some of us have greater vitamin D requirements than others.
0:06.37 Should I offer online nutrition classes?
Before I get into the details, though, I want to share with you an update on something that I’ve been thinking about ever since I got back from AHS. And that is, should I be offering nutrition courses online – independent nutrition courses online? I had several people at AHS approach me about this topic. And it would seem from talking to people that there is some demand out there. If I do offer these courses, they will not be cheap, but they will be incredibly awesome in terms of not only the content that you get, but the tools that I would be providing to help you really master that content and use it. And they would be courses geared at the basics of macronutrient and micronutrient metabolism, so energy metabolism, carbohydrates, proteins, fats, vitamins and minerals. Tying the basics into – always getting into detail with the basics, but tying them into the practical applications – you know, what can we do with this information in a practical perspective? But in this case, you know, the way that this would be distinguished from, say, any of my free content or any of the just straight-up practical how-to content is they would really be scaffolded in a way that would provide a systematic foundation, so that everything becomes maximally understandable. So, you know, particularly if you’re someone who listens to some of my technical information and is like, wow, you know, the 50% of that that I understood was phenomenal, but it would be awesome if I actually had the background to get that. And kind of start from the ground up and provide a very secure foundation to master all this content and really understand what to do with it. If I were to do this, I would be offering two tiers of pricing: one that is – again, none of these would be cheap, but the lower tier would provide incredible state-of-the-art automated feedback where you would provide – not only would you get content but you would get guidance, it’s just that it would be automated guidance that’s built into a system where the system actually really holds your hand, assesses your performance, fully explains everything about how you could strategize to improve your performance. And then the other tier – the higher-priced tier – would be providing you personal hand-holding. And that, of course, I would need to limit to maybe 30 people at a time, so I could actually offer the guidance that would be available. But this is – it’s something I’m thinking about, I’d love to hear your feedback about, you know, whether you think that’s a good idea, whether it’s something that you’d be interested in. So if that’s something you’re interested in, leave a comment at ChrisMasterjohnPhD.com/24 and let me know what you think. Alright, so let’s get down into the nitty-gritty.
0:09.49 This will start off sounding like it’s about racial groups, but it’s really about individuals.
Now as I start walking you through this topic, it’s going to seem like this is about racial groups, or it’s about different groups of people. By the end of this, it should become apparent that this is not actually about racial groups, or any groups, it’s really about individuals. But looking at racial groups is going to provide an excellent foundational perspective to really make sense of this information going forward. And it’s also going to illustrate how it has been easier for us in the past to assume certain things about the differences between racial groups that may not actually be true.
0:10:34 Blacks in America have lower 25(OH)D than whites.
So first of all, let’s start with the observation that if we look at black people and white people in America, black people have lower 25(OH)D, which again is the marker of vitamin D nutritional status. Now to take one particular study that I looked at in detail to illustrate this, that I’ll keep coming back to again throughout this talk, this one study – and I’ll link to the reference the show notes – but it was a study of 105 black and white adolescent American girls. And the black girls had lower 25(OH)D than the white girls. It was about 33% or one third lower. And in fact, if you look at the cutoffs for 25(OH)D, where it says are you in the optimal range or are you suboptimal or inadequate, those cutoffs are around 30 to 32 ng/mL. The average for the white girls is actually slightly above that mark. Again, that doesn’t mean that all the white girls are above that mark, it means, you know, the average is. So the distribution – some are going to be adequate, some are going to be inadequate, but the average is actually above the adequate line. And for the black girls, the average is slightly higher than 25 ng/mL, which actually puts the average in the deficient category. So you could – if you’re interpreting this simplistically and you’re just sort of assuming that that cutoff really can be applied to – across individuals in this manner, what you would say is that the average white girl has adequate vitamin D status, and the average black girl does not.
Now this one – I’m giving you specific data from one study but this is broadly representative in general of consistent findings that in Western society – now, we will eventually see that this is true across the globe, but consistent findings that we have considered totally non-controversial for a long time that, for example, blacks in the United States have lower 25(OH)D than whites in the United States.
0:12:52 The conventional hypothesis explains this as dark skin being poorly adapted to these latitudes.
And over the course of the last century we’ve had this hypothesis – this evolutionary hypothesis for why this is true, come up over and over again. And it’s been repeated so often that it’s kind of become conventional knowledge, at least within the community of people who talk about vitamin D, who are conscious of vitamin D, and yet there are a lot of problems with it that have never really been addressed or resolved.
0:13:17 Genetic evidence suggests light skin began evolving long after the migration from Africa.
So this conventional hypothesis is that white skin evolved as a means of obtaining adequate vitamin D from sunlight once humans migrated out of equatorial Africa. And then, secondly, black Americans have skin color that’s adapted to equatorial regions, but are living in regions that are distant from the equator and are thus displaced from their region of ancestry and intrinsically predisposed to vitamin D deficiency, because their skin is not adapted to the environment at this latitude. Now this, you know, if you just think about it on the surface, this pretty much makes sense, right? So if you imagine that humans evolved initially in equatorial Africa with dark black skin, and you assume that that makes it more difficult to get adequate vitamin D from the sunshine, particularly at latitudes that are removed from the equator, then you can imagine that as humans migrated away from the equator, their vitamin D status declined. This would predispose them to various problems that would interfere with reproductive fitness, so for example if their – you know, as an example, if women were developing pelvises that were not as well developed because of vitamin D deficiency, it may make it harder to have children. If their vitamin D status was declining, they may not have enough vitamin D status to – in the third trimester to optimally mineralize the fetal skeleton, and so on and so forth. And so therefore, that would put selective pressure on people to develop lighter-colored skin that would be able to get enough vitamin D at that latitude, so that at these removed latitudes as the skin would lighten, then vitamin D status would be closer and closer to what was obtained at the equator. So on the surface, that make sense. As well, it’s not like there’s zero evidence for this idea, either. So we know, for example, that if we take people who have more melanin in their skin, they take a longer time to reach maximal vitamin D synthesis. And we also know that there are several small studies where it was shown that when people moved out of equatorial Africa or similar regions to, for example, the United States, vitamin D status declined.
Now, there are a few problems with this. So just in terms of plausibility, before we get to the actual data, it’s not actually obvious that we need to maximize vitamin D synthesis. Clearly it’s the case that there’s some optimal amount of vitamin D that we need. But humans – at no point in history would traditionally living humans ever be expected to maximize vitamin D status, because traditionally humans sought refuge from the midday sun because it was so hot, and because it was dehydrating and because it was exhausting. Additionally, if we make the observation that someone migrates from one place to another and their 25(OH)D declines, that could be because of the latitude, but it could also be because of a change in lifestyle. For example, more indoor living. It could also be from a change in diet, for example calcium intakes, vitamin D intakes, probably intakes of numerous other nutrients and foods can affect 25(OH)D status as well as vitamin D input.
But there are bigger problems than that, that are really fundamental. So let’s take for example the evolution of light skin. The current genetic evidence that we have is that the selection for genes favoring light skin occurred independently in Europeans and East Asians, in both cases around 10,000 to 20,000 years ago. By contrast, modern humans most likely migrated out of Africa over 100,000 years ago, with possibly – some arguments 50,000 years ago and some arguments saying that actually there wasn’t one clear migration, but it was several migrations, or that we sort of evolved independently in many regions and then came together, and so on. But no matter how you splice it, the migration out of Africa was occurring long before the evolution of light skin. And that kind of – you really have to ask the question: if vitamin D status was declining as we migrated out of Africa, and that was having enough of an effect on reproductive fitness to drive selective pressure to lighten skin, why didn’t that selective pressure occur less recently or more anciently than this 10,000 to 20,000 years? What can explain this 80,000 or 90,000 year gap between the migration out of Africa and the evolution of light skin?
0:18:39 Aggregate global 25(OH)D data do not support the conventional hypothesis.
Next, let’s actually look at the combined data across the globe. So this particular set of data I did actually reference years ago in a blog post called “Problems with the Latitude Hypothesis”. And I learnt about this when I was reading the actual massive report from the 2010 dietary guidelines that everyone was criticizing as soon as it came out, clearly before they read the 999 page report. Anyway, if you look at this meta-analysis of 394 studies including over 33,000 people across the globe, what you see is that for Caucasians, the further you get away from the equator, the lower the 25(OH)D gets. But for non-Caucasians, that’s not true. For non-Caucasians, the average 25(OH)D pretty much stays stable from equatorial regions to temperate regions, all the way – you know, as far away from the equator as you can get and still have statistics for non-Caucasian populations. The 25(OH)D basically doesn’t budge.
0:20:05 Caucasians have higher average 25(OH)D than non-Caucasians at every latitude; Caucasians have higher average 25(OH)D at temperate latitudes than non-Caucasians have at equatorial latitudes.
Now, you can look at this another way and compare Caucasians and non-Caucasians. And what you find is that Caucasians consistently have higher 25(OH)D at temperate latitudes, they have higher 25(OH)D at equatorial regions, no matter where you are, Caucasians have greater 25(OH)D than non-Caucasians. But now you can take this even further, and you can say that non-Caucasians at the equator have lower 25(OH)D than Caucasians do at temperate regions. You could almost – the only place that you don’t see that – that that maybe doesn’t hold true is, there’s not a lot of data for the Arctic Circle. But maybe at the Arctic Circle, Caucasians develop 25(OH)D – and we don’t really have – if you extrapolate the lines up to the Arctic Circle, that would be the point where the average Caucasian 25(OH)D is equal to the equatorial non-Caucasian 25(OH)D.
So, when you look at the aggregate data you don’t see this trend that makes – that really makes any sense with the idea that we developed light skin when we moved out of the equator in order to maintain the 25(OH)D that we had with dark skin at the equator. Because Caucasians have higher 25(OH)D even at a temperate regions. So if it’s the case that skin color is driving the difference in 25(OH)D, what it’s driving is higher 25(OH)D in Caucasians everywhere. And skin color is not driving lower 25(OH)D away from the equator in non-Caucasians. So that’s a major problem with the conventional hypothesis as well.
Now, there’s another problem, which is that if we actually delve into more nuanced measurements in people who are not white, who are not Caucasian, then we start to see other problems that arise with this perspective.
0:22:32 Blacks in America have higher bone mineral content than whites.
So let’s come back to the study that I mentioned at the beginning with 105 black and white adolescent American girls. In that study, as I told you before, the black girls had 33% lower 25(OH)D than the white girls. But they had 8.6% higher total body bone mineral content. Now, bone mineral is not the be-all end-all of why vitamin D is important, I get that. And 25(OH)D is not the only thing that affects bone mineral content, I get that. However, the threshold for adequacy that the laboratory reference ranges use is set because if you look at a cross-section of people and you look at, as their 25(OH)D increases, what happens to their parathyroid hormone, the argument is that in the lower 30s is when you see parathyroid hormone or PTH maximally suppressed. And the reason you want PTH maximally suppressed is because elevated PTH causes bone resorption. So the whole logic around the reference range is that the amount of 25(OH)D you need to maximally suppress PTH is good for your bones, because maximally suppressing PTH reduces your reliance on bone resorption to meet the gap in the vitamin D-calcium economy. So in other words, if you’re not getting enough vitamin D and calcium, you will elevate PTH and that will help you get calcium out of your bones in order to supply the rest of the body’s needs. So if the whole logic for setting that threshold of adequacy is to maximally suppress PTH, and thereby remove any unneeded burden on bone for supplying calcium to the rest of the body, then it should at least cause us to think twice about the conclusion that these black girls on average are vitamin D deficient, if their bone mineral content is higher than the white girls in that study.
Now, moving forward, I’m going to assume a little bit of background in the physiology here. And if you want to understand the background in detail, you can go to ChrisMasterjohnPhD.com/9. I talked about the system – the hormonal system that regulates the vitamin D-calcium economy in great detail there. And I also incorporated the concept of phosphorus. Also in the YouTube video associated with this podcast at ChrisMasterjohnPhD.com/24, I will talk about the system in a little bit more detail, just because in the YouTube series, in the videos I haven’t really talked about that physiology and it is helpful to see the pathway on the screen while you’re listening to it. But I’m not going to go over it here. What I’m going to say is, as we move forward in talking about the differences between different people, just keep in mind the concept that 25(OH)D is the metabolite of vitamin D that we look at as a marker of nutritional status, and calcitriol or 1-25-dihydroxyvitamin D is the fully activated hormonal form. In fact, you know, this is generally oversimplified because 25(OH)D does have biological activity. Calcitriol has about 1000 times more activity, but calcidiol and calcitriol are – calcidiol is present in the blood at a thousand times the concentration as calcitriol. That’s probably somewhat similar in cells – if we were to assume that, then actually calcidiol and calcitriol are both impacting the biological activity of vitamin D.
0:26:19 Calcitriol dominance favors getting calcium from our food, while PTH dominance favors getting calcium from our bones.
So, but let’s simplify that and say that the more calcitriol that we have, the more biological vitamin D activity that we have. And then, finally PTH or parathyroid hormone is the hormone that reflects our body’s own perception that the vitamin D-calcium economy is inadequate. So if you have a deficiency of vitamin D, or you have a deficiency of calcium, what you get is transient dips in serum calcium. Your parathyroid gland continuously monitors that and whenever there’s a dip, it makes more PTH. That more PTH helps activate calcidiol to calcitriol, but also has its own effects to help you conserve calcium. And the main difference between relying on more calcitriol versus more PTH is that more PTH means you’re gonna have a relative shift in the burden of supplying serum calcium from your intestines – meaning away from absorbing more calcium from your food and toward your bones, meaning you’re gonna eat away your bones and you’re gonna release calcium into the blood. So as we move forward, consider the question that if there is a way to get more calcitriol without the need for PTH, that is going to be good for the bones and remove that burden from the bones.
Alright, so – now let’s look at some of the genetic variation that we’ve identified in African-Americans and white Americans.
0:27:59 Genetic variation in the 1-hydroxylase can account for the difference in 25(OH)D between blacks and whites in America, but this has nothing to do with skin color or racial groups in the way we have socially defined them.
So according to one study that I will link to in the show notes, there are several genetic variations in the vitamin D pathway that contribute to variation in 25(OH)D among African-Americans that have nothing to do with melanin, nothing to skin color. And those include 7-dehydrocholesterol, which is the precursor to vitamin D when we make it from the sun; 25-hydroxylase, that’s the enzyme in the liver that activates vitamin D to 25(OH)D; and vitamin D-binding protein, that protein that carries 25(OH)D in the blood. But I’m gonna focus here on the 1-hydroxylase, which is the enzyme that converts 25(OH)D to calcitriol, and that enzyme is primarily expressed in the kidney, and the kidney is the main organ that’s contributing to the activation of calcidiol to calcitriol that accounts for circulating calcitriol levels in the blood.
And if you just take that one gene, what you see is that there is ancestral allele, and then there is a variant allele. And if you look at white Americans, half of white Americans have at least one of the variant alleles, and a relatively large but nevertheless – I should say a relatively substantial minority are homozygous for the variant allele. And relatively unsurprisingly, this is not anywhere near as true for African-Americans, so overwhelmingly African-Americans are homozygous for the ancestral allele and about maybe a quarter of African-Americans or a little bit less have at least one of the variant alleles, and a tiny sliver are homozygous for the variant allele. And if we look at white Americans who have the variant allele and African-Americans who are homozygous for the variant allele – now this is just a sliver of African-Americans, but they actually have the same 25(OH)D. So if you look at it that way, you could say that this one variation can fully account for bringing 25(OH)D to an equivalent level between African Americans and white Americans. And that’s remarkable, because it has nothing to do skin color. So it has nothing to do with that conventional hypothesis about evolving light skin as we migrated away from editorial Africa so we could have adequate vitamin D in those regions. This is an enzyme that is not expressed in the skin primarily, it’s expressed in the kidney, that has nothing to do with skin color. And it has nothing to do with the amount of vitamin D that you produce. It has everything to do with the rate at which you convert 25(OH)D to calcitriol.
Now there’s a remarkable other thing that – and this is one case where might be easier to follow this on the YouTube video, because you can actually see the graphs of the data that I’m talking about. But one of the remarkable things as well is that this genetic variation has no effect on 25(OH)D in white Americans. Now, how can we make sense of that? Well, I mean, there could be the slight possibility that this is not a cause-and-effect relationship – that’s probably very unlikely because it’s so biologically plausible that this enzyme would affect 25(OH)D, and because it’s – no one chooses to have a certain genetics, so it’s not going to be confounded like dietary studies would by selective choice. So probably this is a cause-and-effect relationship.
So what that leaves us with is, there is something about the context in which the gene is operating in that’s different between African-Americans and white Americans. And that could be differences in other genes, but it could also be differences in environmental factors, in lifestyle factors. So one of the problems in interpreting that is that there are, you know, maybe a dozen studies looking at this specific polymorphism and associating it with – or not associating it with disease outcomes. A couple studies on 25(OH)D associations and nothing – practically nothing, certainly nothing in vivo about what mechanistically does this variation do to that gene. So I need to speculate a little bit here to try make any sense out of this. And what I would speculate is, let us suppose as a thought experiment that what this genetic variation does is allow someone to produce more calcitriol when their calcium intake is marginal without as much need for PTH to respond. Now, why might we want that system to be like that? Well, it could be that in people who were chronically exposed to lower calcium intakes throughout their evolutionary history, they would have selective pressure to be able to absorb more calcium from their food, which is what happens when calcitriol is dominant, and take out less from their bones, which is what happens when PTH is dominant. Because having a poorly mineralized bone structure is really bad for your reproductive fitness, that should be obvious. Whereas in people who are chronically exposed in their evolutionary history to a higher calcium intake, everything is suddenly changed. Because if calcium intake is chronically high, then you actually are never exposed, or you’re not consistently exposed to this PTH dominance that is taking calcium out of your bones. And so you remove that selective pressure to try to be able to make enough calcitriol because it becomes not as important – if you’re always feeding tons of calcium in the system, you don’t actually need to make calcitriol as much. And so if on rare occasion PTH gets ramped up to make that calcitriol because, oh, you know, there was a period of time where you didn’t have that calcium, then as long as that’s not chronic and consistent, it’s not gonna have negative effects on your bones that will negatively affect your reproductive fitness, because your just gonna replete that skeleton whenever you’re over that period of calcium deprivation.
0:35:02 Calcium intake could influence how the genetic variation translates into 25(OH)D.
So let’s apply this to the comparison of white Americans versus black Americans. If you look at – and in this case I’m looking at the National Health and Nutrition Examination Survey – I’ll put the reference in the show notes – but this is looking at daily calcium intake. And actually this paper reported it by osteoporosis risk, and they gave people low, modern and high osteoporosis risk. No matter what risk category you look at, African-Americans – in this case they use the term blacks and whites, you know, these terms are used very sloppily and just, kind of, different papers will use different terms – I won’t go into that here, it’s a topic for another time. But in this case, so let’s take the high osteoporosis risk category. The total calcium intake from whites is just over a gram, and the total calcium intake for blacks is just over 600 mg. So that’s about 42% lower. If we looked at any other category, moderate is 907 mg versus 473; if we looked at low risk, 953 mg versus 578 – it’s a pretty consistent trend that blacks on average are consuming about maybe 60% of the calcium as whites are. And part of that is because of lower rates of calcium supplementation, lower average rates. Part of that is because of lower dietary intakes. And one of the reasons that would be plausible to suggest for why dietary calcium intakes differ is higher rates of perceived lactose intolerance among blacks. Now if you think about this for second, compare that to what I was saying before about the genetic information – or the genetic variation – and compare that to what I was saying before about, you know, a speculative evolutionary hypothesis for this.
0:37:14 This does not affect white 25(OH)D, and it could be related to calcium intake; ancestral calcium intake could have mediated selective pressure on the relevant genes.
What we could see is, why does the variant allele have such a profound effect on African-American 25(OH)D status and not in white Americans. Well, it could be because white Americans have a higher calcium intake. And so maybe you need to see this in the case of low calcium intake to actually see that difference come to light. So it would be interesting to see more studies that look at this in different racial groups that then start teasing apart what happens if you stratify people by calcium intake, what happens if you stratify people by other genetics that might be involved – I think it’ll be a while before we see that evidence. But let’s keep this hypothesis in mind as – first I’ll go look at some other data, but I’ll come back to this hypothesis that calcium intake could be driving not only the effective gene but also the appearance and incidence of these genetic variations as well.
So now let’s come back to the study on blacks versus whites in these 105 girls that I – adolescent girls that I referenced at the beginning.
0:38:32 Blacks in the United States have higher average calcitriol and a higher average calcitriol-to-PTH ratio than whites.
So not only is there bone mineral content a little bit higher in the black girls than in the white girls, but also their calcitriol is 26% higher. Their PTH is not different, but if you were to calculate the calcitriol to PTH ratio, it’s almost 13% higher in the black girls than in the white girls indicating, that the producing more calcitriol with less of a need for PTH. And if you combine this with the dietary data, that’s probably the case despite the fact that – I don’t think they reported it in this particular study, but despite the fact that these black girls were probably consuming less calcium. So that’s consistent with the idea that there is some genetic factor that’s allowing them to produce more calcitriol with less of a need for PTH in the face of lower calcium intake. And that could account for why they are absorbing more calcium – presumably absorbing more calcium from their food, and taking less calcium out of the bone.
0:39:38 Similar differences between Inuit and Danes: lower 25(OH)D, higher calcitriol, and lower PTH; a traditional diet raises 25(OH)D, raises calcitriol further, and suppresses PTH further.
So let’s shift gears and look at a different comparison. So this is a study that looked at 134 Greenland Inuit and compared them – excuse me, 134 total people, comparing Greenland Inuit and Danes. And they separated the Inuit according to whether they were eating their traditional diet or not. And if you look at 25(OH)D, it is considerably lower in the Inuit on the Western diet compared to the Danes on a Western diet. And we’ve known about this as well, and we’ve looked at this, and in this case the hypothesis hasn’t been that the Inuit have a skin color that’s poorly adapted to their region; it’s that they’re living in a region that humans are poorly adapted to. And no one should be – no one can live in the Arctic and get adequate 25(OH)D, so the conclusion has been that everyone living in the Arctic Circle is deficient in vitamin D.
Now, however, if you take this more nuanced and sophisticated approach that we’re dealing with here, if you look at calcitriol, it’s higher in the Inuit eating a Western diet than in the Danes eating the Western diet. And if you look at PTH, it’s lower in the Inuit eating a Western diet than it is in the Danes eating a Western diet. Now what happens if you put the Inuit on a traditional diet? Well, the 25(OH)D goes up, so that it’s equivalent to the Danes. But calcitriol goes up even further, and PTH goes down even lower. So again, this suggests that the Inuit, when compared to Danes, have some kind of genetic adaptation to producing more calcitriol with less of a need for PTH.
0:41:22 Asians have lower 25(OH)D than whites in Hawaii.
Now let’s look at Asians. There was a study in Hawaii where students and skateboarders – 93 of them – were exposed to the Hawaiian sun with 22.4 hours per week of unprotected naked sun exposure. So this is – excuse me, total unprotected sun exposure, and adjusted for clothing, just around half their body was exposed, and so that was 11 hours per week of full-body adjusted, full-body naked unprotected sun exposure. So you would think that these people were getting enough sunshine. And if you look there, the whites had 25(OH)D that was 37 ng/mL, the Asians had 25 ng/mL. It was one third lower than the whites. Those numbers should start to sound familiar now, because that’s almost the exact decrement in 25(OH)D that we saw with blacks versus whites. And for multiracial people living in Hawaii that were white and Asian mixed, it was intermediate, so it was 29 ng/mL.
0:42:44 The references ranges may in effect be applying average white requirements to drive recommendations for everyone.
And so when we look at these individual studies, it starts to seem like it’s not one particular racial group compared to whites, but it’s actually whites compared to everyone else in the globe that seem to be adapted to this higher 25(OH)D. And that’s a real problem, because when we set the reference ranges for what constitutes adequate 25(OH)D, you know, it’s not the case that that’s all set on white people, but it is the case that, you know, if you take a random sample of people in the United States, you’re going to have 70 or 80% white people that are driving the average. Ad so when you just take the average of everyone, you’re pulling together people who might have a different 25(OH)D, and you don’t see these potential differences. And so it could be the case that we’re using 25(OH)D from studies where white people are driving the average and trying to apply it to everyone, which is not good practice.
0:43:49 The Maasai and Hadza have higher 25(OH)D, but this may be due to higher calcium intakes, and/or higher ancestral calcium intakes that influenced their genetics.
Now there is a caveat to this. And that is that if you look at the Maasai and you look at the Hadza – the Maasai are a cattle herding tribe in equatorial Africa, the Hadza are a hunter-gatherer tribe in equatorial Africa – you will see that their 25(OH)D is 48 and 44 ng/mL on average in those two groups. Now, granted, if you were to adjust the methodology that was used in that paper and compare it to – standardize it to the methodology that’s used in most of the other papers, that’s gonna drop down to 37 in the Maasai and 33 in the Hadza. But nevertheless, that’s a lot higher than what we see for non-whites, and it is pretty similar to what we see for whites. So why might this be?
Well, consider first of all the calcium intake in these two groups. The Maasai are cattle herders. They consume massive amounts of calcium. The Hadza, although the Hadza are not cattle herders, they consume very large amounts of a plant that – I have no idea if I’m pronouncing this correctly, but it’s baobab. And many researchers consider it one of their five food groups. It’s extremely rich in calcium and constitutes – of course, their diet is gonna vary seasonally, but it constitutes on average 14% of their calories. And so the Hadza, because of this particular plant food, have very high calcium intakes.
So I would offer two suggestions to explain this. One could be that the high calcium intakes themselves are driving the higher 25(OH)D. Because if you have a high calcium intake, you’re sparing the need to convert 25(OH)D to calcitriol. But the other possibility is that the genetics are different in these groups. I’ve never seen the relevant genetics assessed in these groups. But if we come back to the speculative evolutionary hypothesis that I’ve given you before, which is that groups that historically consume high calcium intakes, that’s gonna favor – or we could say that’s gonna remove the selective pressure needed to be able to make more calcitriol with less PTH. And so it may have – again, you know, the genetics of the of the 1-hydroxylase, the enzyme in the kidney that converts calcidiol to calcitriol, has nothing to do with skin color. So it may be the case that it has more to do with historical calcium intakes. And if you look for example at most African-Americans who trace their ancestry through the Hellenic slave trade, if you compare that to – or if you just look at the populations where that comes from, you’re looking mostly at populations – at agricultural populations on the coast of Western Africa, who – and I’m not an expert on the ethnography here, but as far as I know, grains were very high in the diet, dairy was not very high in the diet. And if you look at Africa in general, what you see is that genetic diversity is higher there than anywhere else on the planet. So if you’re then going to go to Eastern Africa and find a cattle-herding group that is occupying Kenya and Tanzania like the Maasai are, there’s no reason to think that their genetics are gonna be any anything like the idiosyncrasies that we would see in populations on the western coast of Africa, because their evolutionary history is completely different in that region. And if their evolutionary history is one of cattle herding, then – and their genes are impacted by that – then even though their skin color and their melanin content is going to be similar to other groups in Africa, it could very well be that their genetics of vitamin D metabolism look a lot more like Western Europeans who have a history of dairy herding in their ancestry.
Now, I don’t know whether that’s the case. And, again, I don’t know the genetics of these groups, I don’t know mechanistically exactly what these polymorphisms in the 1-hydroxylase are doing.
0:48:24 Non-whites are probably adapted to lower 25 (OH)D than whites on average, but it is individual genetics rather than racial groups that are relevant.
So all of these things tie together in a speculative fashion to suggest that people who come from traditionally dairying cultures may on average have different 25(OH)D than people who do not. And that it actually isn’t about whether you’re white or you’re black or you’re Asian, but it’s about the actual specific ancestry involved. And then, when you actually look at any of these particular groups, what you see is even then, it’s about the individual; it’s not about the group per se. Because even if you look at the group of African-Americans that I was citing before, where they found that the variant allele for the 1-hydroxylase was present in this tiny sliver, well even that tiny sliver has that variant; even white Americans – half of white Americans have the genetics that are associated with the ancestral allele that dominate in African-Americans. So no matter what group you’re looking in, there are always individuals who have these different alleles represented, and you have to try to understand the individual.
Now, what you can’t do right now is just look up on 23andMe what is my polymorphism for this, I will then use that to determine how much vitamin D or calcium I should be taking in. And that’s because we don’t even know really the mechanistic basis of these associations. We don’t know what the polymorphism is doing. So it’s a really bad idea to try to prescribe things based on the genetics. But we also don’t know what does the big picture look like when all the genetics are interacting together? Because clearly there are a lot of genes that are potentially involved, there are a lot of genes that are associated with 25(OH)D. Until we’re able to create some sort of algorithm that looks at the combined effect of all of those genes, and in order to do that we really need to know not only what all of the genes are, but how they interact in different combinations. Then – only then will we even be able to diagnose a predisposition. At that point it’s still a predisposition, so until we have an algorithm that then feeds in all of the dietary-environmental-lifestyle factors that can affect the impact of those genes, then we don’t have grounds for prescribing a certain amount of vitamin D or calcium for a certain combination of genetics and environment and lifestyle and diet.
And then, you know, if you think about how complicated this is, we’re probably never going to develop that, because it doesn’t make sense to develop that. What makes sense is to try to create this picture using blood measurements and using comprehensive diet and lifestyle analysis, and using the genetics – try to create what is the big picture and what’s actually happening in this individual’s body.
So moving forward with practical conclusions, I do think it’s true that people of non-white ancestry have a lower 25(OH)D requirement than people of white ancestry. However, that is an average, and so it doesn’t really have practical significance, except when thinking in terms of probability. When you’re actually treating a patient, or when you are an individual seeking information about your health, it becomes much more relevant what is going on in the individual. In that case I think it will eventually become useful when we understand the genetics more, to look at the polymorphisms within an individual. I don’t really think we’re there yet at this time, but what will always be in my opinion the central measurements that we’re looking at are diet and lifestyle analysis and not only 25(OH)D but also PTH and probably calcitriol in the blood.
So if we’re looking at PTH and calcitriol, I would say that – first of all, I mentioned before that 25(OH)D is 1000th as active as calcitriol, but it is present at 1000 times greater concentration in the blood. They’re reported in nanograms per milliliter for 25(OH)D or picograms per milliliter for calcitriol.
0:52:59 25(OH)D + calcitriol can be summed for a biological activity index.
And so because the units are different, it actually is the case that you could – you could in theory add – just sum up calcidiol plus calcitriol in the blood and come up with an index of the biological activity of vitamin D. I don’t think that’s useful at all for diagnostic purposes right now, but I would encourage clinicians who are listening to this who deal with a large number of patients, I would encourage you to collect data on the sum of those two parameters and over time see whether it correlates with any clinical or health outcomes. And I also think it would be really useful if in research studies we started reporting this as an index, you know, certainly – I can’t promise that that has utility, but it certainly seems like it should have utility, and so it would be nice to start collecting information on it. But what I do think has very clear practical relevance now is this point I’ve been harping on over and over again, about PTH. If you measure PTH, what you’re doing is you’re asking the question, how does the conventional standard that’s used to set the bottom of the threshold for the vitamin D adequacy, how does that actually apply to me and my body?
0:54:09 PTH should be in the lower half of the reference range.
And the PTH ranges from 10 to 65 as normal, that’s in picograms per milliliter. That means normal as, you don’t have a parathyroid disorder. But within that range, it appears that – that information isn’t perfect but based on what I have, I would tentatively say that PTH in the lower half of that reference range, at or near 30 or preferably below 30, would probably be representing maximal suppression, and above 30 would probably indicate that you have room to go in terms of getting more vitamin D and more calcium to suppress PTH further. And the further up that gets from 30, the more I’d be concerned. So I would find 40 pretty concerning; I would find 50 or 60 really, really, really concerning. And I think that can add a lot of value to looking at 25(OH)D, certainly if 25(OH)D is 10 ng/mL. I don’t think you need to do more measurements to say, look, this is borderline rickets or osteomalacia. You need to get yourself out of that level of risk. But when you’re looking at something like 25 ng/mL, it starts to become really unclear – you know, 25 ng/mL looks like on average it’s probably adequate for Asians, on average may well be adequate for African-Americans, for Inuit. So – and given that, it’s probably adequate for some white people as well. And so I think that’s really the gray area where measuring PTH would be really helpful to try to greater discern whether that’s meaningful or not. So, for example, if your 25(OH)D is 25 ng/mL and your PTH is 15, I find it really unlikely that you need more vitamin D and calcium coming into your body, because your parathyroid gland is the resident expert on that particular issue, and your parathyroid gland – if its decision is that you’re not deficient in vitamin D and calcium, you’re probably not.
0:56:20 Magnesium deficiency could confound the PTH measurement, but it probably has to be extreme.
Now, one caveat that should be thrown into the mix is that if you have someone with pretty bad magnesium deficiency, that’s gonna compromise their production of PTH. But from what I’ve seen, both looking at consulting clients, looking at the data, talking to people, I really think that the average person in modern society is not deficient enough in magnesium for that to come into play. Overwhelmingly, when we look at people who are at increased risk of osteoporosis, people who are deficient in vitamin D and calcium, their PTH is elevated. And so you can say, well, all of those people need more magnesium – maybe that’s true. But if that’s true, it’s not so true that it interferes with this use of PTH.
Now, I do think there are extreme scenarios where if someone has multiple deficiencies going on and that magnesium deficiency is really bad, that can start to cloud using PTH as a judgment in this case. So again, so the normative interpretation here would be, if you’re in a gray area where you’re 25 or 30 ng/mL, you definitely want to look at PTH and make sure that it’s in the lower half of the reference range.
Okay, given that, I think that is sufficient to conclude this. Remember that the show notes are at ChrisMasterjohnPhD.com/24. That’s where you’ll find the YouTube video – the YouTube video will be really useful if you had any trouble following along with the physiology or the data. I will have slides up there that provide the pathways and the graphs to look at that. Eventually, when it’s ready, the transcript will be up at that same location, and the links to all of the relevant material and other resources, references and blog posts that I talked about will all be found at ChrisMasterjohnPhD.com/24. Remember the idea that I mentioned at the beginning about nutrition courses: let me know what you think of that. It’d be really cool to see what my audience thinks of that when I’m thinking about whether to move forward with that idea.
Alright, thank you so much for listening signing off this is Chris Masterjohn PhD of ChrisMasterjohnPhD.com, and I will see you next episode.
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