 It's my honor to introduce the individual who is going to introduce our speaker this afternoon. But let me tell you a little bit about the Genomics and Health Disparities Lecture Series. This is the eighth of the Genomics and Health Disparities Lecture Series, which is focused on the dialogue about how innovations and genomics and research technology can impact health disparities. In addition to the National Human Genome Research Institute, the series is co-sponsored by the National Heart, Long and Blood Institute, the National Institute of Minority Health and Health Disparities, the National Institute of Diabetes, Digestive and Kidney Disease, and the Office of Minority Health at the FDA. And I want to thank Dr. Perez-Dobbley, the director of NIMHD who is here in the audience today. Speakers have been chosen by these five institutes and centers to present their research on the ability of genomics to improve the health of all populations. The speakers in this series approach this problem from different areas of research, including basic science, population, genomics, and translational and clinical research. To introduce our speaker today, I'd like to invite my colleague, Dr. Charles Rattimi, who's the chief and senior investigator of the NHGRI Metablet Cardiovascular and Inflammatory Disease Genomics Branch and director of the Center for Research on Genomics and Global Health. Thank you. Charles? Thanks. Thanks, Vince. Again, it's a distinct pleasure here to introduce our speaker. I hope I'm advancing this correctly. Okay. Richard Cooper, who is my mentor and I've known Richard for many, many, many years. I think since 1992, so he was the person who trained me to this point, you know, in terms of whatever I do today at the NIH. So Richard, indeed, his work has provided remarkable insight into cardiovascular diseases in different human populations, especially the African diaspora population. I remember one evening when I was doing my postdoctoral work at Loma Linda, I saw an ad from Richard, again, basically in advertising for like an assistant professor of position. And I saw this ad, after I read it, I told myself, this was written for me. And I remember calling Richard, you know, to say that you must have had me in mind when you were writing this ad for a position. The rest is history. I went to Richard for the interview and I got a job as an assistant professor then. And my training really, in a sense, started from that point of view. So I'm sure you probably see some of these when Richard gives a talk, you know, when he starts his talk. What his work has really done for me in terms of my own training is to enable me to have a more critical way of thinking about her disparity in a way that you really have to bring to bear the society within which you are doing this study and how the environment, you know, tracks some of these things. So the very first project I worked on with Richard was this, you know, publication in 1997 looking at the African diaspora populations. And that was my baptism in a sense of doing population work. And I believe I learned a lot from working with Richard, going to different African villages and the Caribbean to do this work. It demonstrated clearly the importance of environmental factors. So that to me is really part of the wonderful training that I received. Also working with Richard, I remember we do talk, like in the evening, in the office, and the following morning, Richard comes back. He has these two or three pages of what we talked about. And I'm always scratching my head, how can you write this quickly? So that was some of the really interesting things that I picked up again from Richard. And his studies really has shed light into understanding, you know, her potential, especially in African-Americans. Because initially when I started working with Richard, you hear all these things. People describe her potential in African-Americans as if it's some kind of difference physiological problem that is almost not, you know, other human beings don't have the same pains. And by doing work in different African populations and in global populations, he was able to put the African-American experience in perspective. And that has stuck with me over the years. One of the things that we share light on, you know, is really this issue of the slavery hypothesis. I remember this publication in Scientific America, which we required, who has now passed away, a good friend of Richard and myself, where there was these people thinking about, oh, the slavery and the survival of African-Americans during the slavery more have selected upon some kind of variance that is put in African-American queries for blood pressure. I remember Richard, you know, saying, Charles, we have to test this out. And we collected these samples and did a genotyping for agiotesinogen. What it turns out is that although the frequency is higher in African, but really the effect was in really tracking blood pressure in a way that would be meaningful. Again, the initial work in this area. So you can see how his work has indeed shed light in this work. So he's well known in terms of his cautionary tells about all of us, how we use race in genomic studies and also biomedical research in general, and also in the societal contest. And that has stayed with me over the years. So again, I want to thank him for that, for that earlier education of how to interpret data, especially in the context of her disparity and race. And Richard has published, again, widely over 400 peer-reviewed publications in different journals. And when it was time to, again, create H3 Africa, I caught on my mentor, Richard Cooper, you see him in that corner right there. Again, to help us think through, how is it that we're going to create this wonderful resource for Africa and to bring to bear his experience. So he has always been there for me and for this kind of work in different African populations. And I want to end with this particular slide here. He got to a point in 1999 when I told Richard that I was going to move to Howard University. That was indeed a very, very difficult time for both of us. This was a picture that was included in the send-off package when I was living at Loyola Medical Center. But the point I want to make with this is that I've always seen Richard a my mentor. He continued to be my mentor and he did not give up on me. What Richard did not realize, although I had a bold face, I was terrified of leaving his shop because he's really the only person I've worked with that has credo me all these years and I was about to leave and go on my own. And so I want to use this opportunity to thank him for the work that he has done in training many African scientists and other international scientists. The insight he has brought into his disparity that I think he will be very convinced of when he comes to this stage today. And also the support for me and my family. So thank you, Richard. And Richard's daughter is here, who again I want to thank for supporting Richard all the way here. So thank you. Very nice. I appreciate Charles. I mean, of course, you have to realize it's a pleasure for me to come here and be introduced by you and see you thrive here in the NIH. And that's probably the most important thing that a teacher wants for students to do well. So I'm not going to talk very much about genetics in the sense of molecular genetics. I'm going to talk about phenotype, which of course is connected to genetics. And I have a separate sub-theme I want to embed around that, which I'm going to start with. But first, and then I will talk about through my trajectory how I've thought about this problem and studied it. So one of the sub-theme I want to add is that we're using these transformative tools, as we call them. And there's this complementary weakness to having so much data is overreach. Somebody who works in artificial intelligence said that any technology that's sufficiently advanced looks like magic, because you don't know the limitations. You don't know what it can do. So we're always pushing at this end of the unknown. And I think to balance our understanding and to use it effectively, we have to be aware of that at all times. So if you're wondering about the subtitle in Chasing the Phantom of Race, it's basically on this subject that whether we can use genomics to get us any closer to understanding something that has been around for a long time, and done plundering of harm, and not very much help. So just to make sure that I'm clear on what the issue of overreach is, this was the European project that they wanted to create a computer model of the human brain. So they put up whatever 1.2 billion and said they were going to, within a year, develop this model. And the neuroscientists all united and said, you know what, we can't really do that, not in one year. We're nowhere near that. So in this case, the scientists themselves were the ones who challenged them on overreach. And another one, which is the area that we work in in public health, is the global burden of disease, which has its goal to summarize all of the health information from countries around the world. But for those of us particularly working in developing countries in Africa, you know, we're not very happy with. They give you this data by age and sex for Mali and Bolivia and all other places where the information is really very scant. And the issue is, with this degree of overreach and public health, are we really improving our understanding or are we confusing ourselves? So we did some work a few years ago in Cuba during the period when the Soviet Union pulled out its trade embargo, trade in the United States increased its trade embargo. So the gray lines here are the data from the global burden of disease. And these lines here are the actual trends in weight. So everybody in the country lost 15 pounds because of food shortage. And what happened was that during that period of weight loss, which is the blue curve here, followed by a period of about four or five years, the death rate from diabetes fell by 50%. So from the other data, you would have totally omitted the significance of this trend. So we need to look in detail at the original data. And then finally, I couldn't resist putting this up on the issue of systems biology and asking about the fundamental rules in complex living organisms. I mean, I understand the technical issues here, but I'm very skeptical that we're going to arrive at fundamental rules. I think the danger is that things are reified so that we make the mistake of thinking that our model that we develop is a thing itself. A thing itself is much more complicated than that. And so what I want to talk about now is what we know about blood pressure, particularly in persons of African origin, and what are the obstacles to really coming to a simple answer on that question. So this is where I started out, University of Arkansas Medical School in Little Rock, Arkansas. It's a lot bigger now than when I was there. And just out of curiosity, I went to the CDC and looked at some of the current data on hypertension in Arkansas. So you see a black-white difference, as you'd expect, though not as large as we'd think in other states. This suburban, urban-rural variant, and then, of course, a pretty substantial social class gradient here. These data are actually clearer in terms of the social class gradients than most of the data, particularly what you see in Haynes. But when I was in medical school, I began to wonder, why did we privilege this particular contrast as being so important? And why did we not recognize that many of the people who were here were here, living in shacks without access to medical care? So that question really was what started my whole interest in hypertension in a scientific career. The other thing that happened to me when I lived in Little Rock was that in 1958, there was school desegregation, and the Supreme Court heard a case called Aaron versus Cooper, and said that the opening date of high school will be September the 15th. As some of you know, this is a major historic event in the Civil Rights Movement, and that particular Cooper was my father, so I was aware of this process and thrown into the whole controversy, being in a public school and having all my friends who were clearly on the other side of this debate, and became aware of how complex and important race is. So I think I later on found this quotation from W. Du Bois, the eminent scholar and the 20th century black scholar, and I sort of said, you know, that's pretty much what I was thinking. I kind of like that idea. So I've kept that kind of as my motto. So just to give you a word at the beginning, and everybody knows this, if you look at the basic measures of health status, you see that the rates are lower in whites than in blacks for every category except COPD. And you cannot get a conclusion that this would be something driven primarily by genetic factors to have that broad scope. Although what's interesting to me is that people who work in each individual discipline will themselves focus on the importance of genetics at times. We'll focus on that without seeing that if you look at it in its totality, that's a very unreasonable prior hypothesis. So just to let you know that there is a structural theory that underlies those of us who look at that the social forces as being the primary determinants of health and the primary determinants of health inequality. So that racial inequality has two key components. There's the racist beliefs in the population that facilitate and allow these things to happen, allow them to be done to our fellow citizens, and they have an economic value. And Du Bois actually said that the main purpose was to create a particular class of low wage workers. And finally there's the major political advantage which I have to say I think we're being played out today, is that there is this false allegiance between politicians or other people based on white nationalism. So this is the, to my mind, this has been the enduring social dynamic within the United States for as long as it has existed. But I always want to instantiate this idea of not being accepted to full citizenship by this example, which is sort of a historical curiosity, but I think it's an interesting one. In 1927 the Mississippi was high in its banks and was going to flood New Orleans. So the people in New Orleans said this can't be allowed, this is before they had the current levee system. So what they did was they dynamited the levees in Mississippi and Arkansas and the Delta, these lands that were surrounded mostly by sharecroppers and black farmers. They dynamited the levees so the river had some place to go and New Orleans was not flooded. But then they had to repair the levee. So people were pressed into service here, black farmers that were not asked and were not paid but were told to come to these camps and essentially gang labor. And the output ingredient is this guy sitting here with a shotgun. So this is just to say that under normal circumstances all citizens seems to have rights in the society. But as soon as so to speak push comes to shove and we're talking about a crisis it's very clear that full citizenship is not given to every member of the society. So this is my first paper which was sort of a, I did this when I was a cardiology resident had zero data or insight but was suggesting the hypothesis that I wanted to look at which was that maybe there's, maybe if we look at the environmental factors we can find another explanation why there's blood pressure difference. And this was the sort of the state of thinking at that time. Paul Dudley White who was the preeminent cardiologist for the first half of the 20th century, Eisenhower's cardiologist had this in a symposium on blood pressure in Chicago. And reflected sort of the standard view at the time but even as recently as the 1990s that idea has still been mooted. Again without feeling like the need to resort to any particular evidence. Simply it was something you could be stated. So this is a study that Charles showed at the very beginning. We were fortunate to meet collaborators from Nigeria and from Jamaica and other parts of the Caribbean and fortunate enough to have the NHLBI fund this study and we collected this, 12,000 people evenly age group from 25 to 65. Is it largest international comparison of blood pressure than undertaken? One of the problems is that blood pressure is very difficult to standardize over time or across locations. It's very hard to train a field staff to use identical methods. So that was one of the main things that we had to focus on in the beginning and having one individual travel to each site and train everybody and measure them to make sure that there wasn't any bias in what they were doing. This was before the day of electronic blood pressure cost. This was the meeting that we had in Ibadin. This guy you probably, some of you may know he's right front and center. He's not hiding from anything. And Babatundir Shota Man who became the Minister of Health in Nigeria and ran one of the big programs for the WHO. Wally Munoz had a cardiology in Cameroon and we had some very talented special people involved in this. That was one of the best things about it. So this is a version of the slide that Charles had. In fact, I'll have to borrow his version. It's much better than mine. But you can see this clear gradient from Nigeria. Cameroon, most of the sample was drawn from a housing project for civil service in the capital city. But in Nigeria, people are still very lean and blood pressure were low. And in the Caribbean, they were pretty similar. As most of you might be know, Barbados is a society with a higher standard of living, higher BMI. So, I don't know how I do that. So if you look at the impact of the standard normal boring risk factors, they do follow this clear gradient and can explain most of the difference across these sites. Now, we just recently completed another, well, it's already four or five years ago, another survey that involved this set of countries. And one of the interesting things to me was that in South Africa, this is from Cape Town, and these are people who live in the townships in South Africa, blood pressure is as high, particularly among men, as they are in the United States. And these men are very lean and physically active, mostly construction workers. And we still get this clear difference for Ghana and Jamaica, so I'm quite convinced that that's real. So it obviously suggests to one that the semi-apartheid nature of the current South Africa situation and the United States are very similar and are driving the same effects. I also had an idea at one point to see what it looked like to compare blood pressures in a whole range of countries, including those from the black African diaspora. So you can see that the United States has lower blood pressures than most of Europe, but blacks are somewhere in the middle for European countries. And one other way of getting at that data without having to use survey data is to look at stroke mortality, because stroke varies, it's correlated to 0.9 with the prevalence of hypertension. So you can see that as we showed before, the blood pressure data show this gradient. And if you put black Americans on there, they're somewhere again in the middle of the distribution for Europe. And nobody has come forward yet, as far as I know, to introduce a genetic theory that the fins might be predisposed to hypertension. And speaking of the fins, I think it's interesting to look at the data before they started on their widespread prevention campaigns. That's a huge difference in systolic blood pressure. And just think for a minute now, we've been totally, completely blind to this phenomenon, right? I mean, blacks are universally known, wherever you go, they're gonna tell you that they have the worst hypertension and that many people are probably at this point sort of a 50-50 split who believe that it has primarily a genetic origin. So I'm just gonna run through a quick set of data here to again show the heterogeneity of what's going on with this phenotype and how difficult it has been to pin down what are actually the differences. I mean, just a simple measurement difference. What are the survey data show us about blacks and whites? And can we get a reliable, stable, reproducible answer to that question? So the cardiac study, many of you may or know, young adults followed over time. So the incidence rate for new hypertension in Birmingham was much higher than it was in Chicago. Okay, it's not a huge sample, but still it's consistent across there and it's also true for women. So the South has a historical meaning which is persisted over time. The other thing is that if you look at stroke rates, whether people who were born in the South or born in the North, there's a huge difference. The difference between blacks born in the South and the non-South is almost as big as the difference between blacks and whites. So the West Coast is, as always, ahead of the curve, stands for the future and shows that many of these things are client change within the United States just simply by changing the place where you live. One of the challenges, which is unfortunately not been really adequately addressed, is to clearly characterize the dietary factors that influence hypertension. I mean, we expect that the majority of the effect, the majority of the causal experience with hypertension is things that you put in your mouth. Sodium, high fat foods, and so on. But since the food intake is so variable from day to day, it's very hard to characterize it accurately. The Intermap study did a much better job than any others and if you just look at the data they collected on dietary intake, you can see that about half of the gradient between blacks and whites can be explained by the nutritional data that they collected. All right, so turning into the psychosocial aspects, David Williams, this was in the New York Times, that's not a bad way to characterize it. I mean, I think it's, I certainly wouldn't dispute its veracity and I think it's something that we all need to recognize and think about from our own point of view. But to study that phenomenon is more difficult than studying nutrition. So this is a meta-analysis of the studies looking at perceived racism and you can see they're kind of wobbling all over the place. The cumulative effect size is positive but I think that if you think about publication bias and other questions, this is not the strongest dataset that we have, but it's certainly leaning in the right direction if that's the way you wanna frame the hypothesis. So one of the things that has been missing in the past is to look at migrants from either the Caribbean or from Africa. About, I think it's eight or 10% of black Americans who now were born abroad and this data is now available from the NHANES surveys. Okay, I'm sorry. Before I get to that, these are data which set up the hypothesis that I wanna talk about. So in the state of Illinois, the birth certificates include the place of birth where the mother was born. So when we went back and looked at the birth weight distribution for the babies of women who were themselves from Ghana and Nigeria, it falls right on top of the distribution for whites. However, if you look at the distribution for their children, the second generation offspring, they've moved down. So this generational resonance in the United States means that people take on more of the appearance of African-Americans. And in some parts of the Caribbean and in Brazil, the gradient between blacks and whites is much smaller. In Cuba, it's almost no and there's still in Brazil and Trinidad, it's not no but not nearly what it is in the United States. These are some data from Brazil just showing that if you actually make these used genetic markers to estimate the proportion of ancestry, you don't find any difference by blood pressure but more of a social class. The data from Brazil I admit are very complicated and Brazil is because of its population history is a very complex society. So we also have moderate amount of data from Canada. Here's the relevant risk estimates, odds ratios and you can see that there is an elevated blood pressure risk among blacks but there's also almost similar for some of the other groups, particularly the Filipinos and South Asians and other data from Canada as well. All right, so the other source of data that we have are migrants to Europe and there's a group in the Netherlands who's been very active on this topic and this is a summary of the data from migrants from other parts of the far flung Dutch empire at one time and from Ghana and you can see that they definitely have a higher risk of hypertension, much higher than you expect in the United States. And this is finally, these are the data from Europe as a whole, looking at all the migrant data and showing that South, the Sub-Saharan African men and women have higher risk of blood pressure and hypertension after taking up residence in Europe. So the data is sort of mixed if you ask me and this has been the question where what would we focus on as being the central aspect of this problem? Well, the data that I would mention before that I think is particularly relevant is to look at persons who were examined in the NHANES survey but who were non-Hispanic black but were not born in the United States. So there are about half of these individuals who came probably from the Caribbean and half from Ghana and Nigeria. So there's a modest number if you add up all of the years of the NHANES. And to me, it's quite interesting that you can see the blood pressure between U.S. born and foreign born blacks is virtually the same. I would have anticipated ahead of time that that would not have been the case but confronted with these data and then you have to then go back to what I'm posing as the conundrum. How can we really even using the phenotype and all of these complex ways of studying the question, how can we come to some sort of comfortable conclusion about is our blood pressure is really higher for some sort of intrinsic biological reason or is it a part of the social process? Because Africans who come to this country confront to many ways the same racial barriers and stereotype that native born African Americans do. We still can't disentangle it completely. So the last thing I don't wanna talk about briefly is just that the idea that there would be genetic predisposition to a complex disorder can be put within some sort of an evolutionary biology framework. So if we know now that there are probably 400, 500, even 1,000 genes that relate to blood pressure, unless you have one or two that have a large effect that are differentially represented in populations, you have to have a whole series of these very genes with very small effects aggregated in one population. Now that wouldn't happen by statistical chance long so it could only happen if there was selection on those traits. So the hypothesis is that Africans would have been selected for a trait that somehow later on led to higher risk hypertension but that trait would no longer be present in all those people who've migrated out of Africa to Europe and Asia and so on. It's just not a viable hypothesis to my way of thinking. And just to go then to the pieces of genetic data that we do have that can make a direct comment on this question, to my knowledge this is the largest study that has been done so far and looked at genetic relative risk in different ethnic groups and in their data the African Americans have the lowest overall score. Again, I'm not waiting this evidence that heavily because it's a long way before we get to a satisfactory way of actually looking to test the null hypothesis but given what we do have there's no support for the idea. So I'm just gonna return quickly to the main idea that I wanna talk about which is this question of overreach. Maybe the other way of saying that would be humility for the biological complexity and suggest to you that I'm an epidemiologist who spent the last count 45, 50 years studying this question and we've looked at it in every plausible way that we could think of and we still haven't resolved the issue of the simple issue of what are actually the blood pressure differences and what can we point to in terms of the very well-known more or less easily measured environmental causes for hypertension. So if you then go from that dilemma, that conundrum and you go to asking something about the molecular basis for differences in a trait like blood pressure I'm suggesting that that's an even more complicated undertaking and that in fact maybe it's something that we probably shouldn't even really frame as a either testable or a very important question because you think about it for a little while why are we really so fascinated with the idea that blacks have higher hypertension than whites? What is the, at the bottom besides that being sort of a social and political interest in something that frames the way we think about other health conditions? Why is that such an important question? So this is just my way of saying that we need to think about not only epidemiology, environmental and social processes in combination with and implicated with the genetic and the biological questions but we also need to ask ourselves once we get to a certain point where we recognize the level of complexity that exists is that some of these questions may for the time being certainly be beyond our grasp. So then just to finish, this is a model that I used in the past, I decided I would resurrect it and looking at this evolution of how we think about population groups, those we categorize by the label of race and how that's evolved over time. So this is sort of the model if it's given as polygenic that say Paul Dudley-White was invoking. We have this downward shift in risk, in genetic risk whether you wanna make it a Gaussian distribution or not that's the format and so that there's a clear separation between those two. Somewhat further on using a different mode of analysis and a much more sophisticated scientific approach anthropologists used to like this one of a branching tree and as Rick Ward, the geneticist we used to work with quickly pointed out this design is completely wrong. If you look at that for a few minutes think about it it's this is completely misrepresentation of the pattern of human relatedness by populations because the people over here should be down here, right? And that's what we've learned in part from H3 Africa from the HapMap and other projects that the great bulk of segregating variation is resident in African populations. So I'm gonna suggest then that this is probably the central image that we now can rely on and use that the great majority of the variation is shared, the great majority is already present in Sub-Saharan Africa and there's plenty of variation Africa which is not shared outside but that's the structure of which these populations are related and we would probably do better to think about the complexity of the conundrums of phenotype and genetics within this context. And with that I'll stop, thank you. Please use the mic. Hello, my name is Saraya, my post back here within NINDS. I wanted to give further clarification on how you saw the trend of more research on how people of African descent may have higher hypertension because of the genetics compared to their social or economic status, where did that come from for you? How did I first encounter the question or how did I come to? How did you first encounter the question, Iya? So as I was saying before, in medical school at the University of Arkansas, the University Hospital served large numbers of black patients who had often had severe hypertension at a young age, some of whom had a stroke because of lack of adequate access to care and so that was where the discourse, the discussion among physicians about why there was more hypertension in blacks than in whites. It was likely a genetic phenomenon. In other words, this reflects acceptance of this historical way of thinking that we're slowly trying to outgrow. And second question is, just trying to understand why do you believe there's more, I guess it's already self-explanatory, but why do you believe there is more research on believing that hypertension is related to genetics compared to socioeconomic status? Yeah, I think that we've, over time, we've achieved a much better balance and people have recognized that if you're gonna talk about genetic causes, you have to study something genetic and so since we have this explosion of the technology and the genome error, that's one of the questions which would be on the agenda and would be studied. I agree that there's probably been less work done on the psychosocial factors, but one of the things you have to realize is that some questions are tractable at a certain historical moment and some are not. You have to have an adequate measurement tool and you have to have an exposure that you can actually reliably measure and unfortunately, for those that we would think would influence long-term blood pressure control through the central nervous system and it's some sort of psychosocial factor, we don't have very good ways of measuring that. I mean, there are certain physiologic measures like sympathetic nerve traffic, but I don't know that there's a lot of important questions out there that we have tools to study in the psychosocial domain. So following up on her question and your talk, should race and ethnicity ever be used in genetics research, in genomics research? I'll take a pass on that question. Well, I think, maybe I'll say the standard answer is that race as a label has enormous explanatory power in this society where people are born, education they get, and so on. So if, since we want to study whole organisms and we know that genes don't exist on a shelf, they only exist when they express themselves in an organism, then we have to consider that aspect of race. The other sort of an obvious thing which we don't really, maybe confront is that the United States is a little bit peculiar because we brought together people from very far geographically away, you know? So it kind of makes sense, I mean, it's sort of obvious who's from China and who's from Nigeria. So it's a label of convenience, it's not without some biological meaning. But I think that's part of this thing that I'm trying to say that the complexity is all these things at the same time. While we think about it that way, we have to also recognize that we're in an intellectual environment where race has taken on a lot of other sorts of meaning. About the person, you know, everything, like I say, from the full citizenship to are they really people who we would want even to invite into full citizenship? And so we need to, I think we need to, I don't think there's any particular value myself in trying to explain a very specific racial difference that we don't have some prior evidence for, like Apoel 1, renal disease, sickle cell, I mean, you know, these are things which clearly we're gonna be guided by labels, they're gonna be relevant to us. So there's no easy out. I mean, this society is stuck with race, stuck with race, stuck with racism, and all of its consequences and complexity, and so those of us who do science are stuck with it too. Given that most African-Americans come from Western Africa in terms of the historic population, but there is a lot of genetic variation within Africa and different migration patterns, how well does blood pressure variation understood within the African continent as a whole? And both from either genetic or social factors? Yeah, that's a good question. I mean, we do know that as people move to the city primarily and begin to adopt a diet that's high in sodium and gain weight, blood pressures are going up, so which is, again, that's obviously the normal phenomenon that we're seeing everywhere, but I think the state of epidemiology for blood pressure survey in Africa is very weak. A lot of these studies have been undertaken by groups that haven't had as much training as they might need, and just that's also to add that it took the NHANES survey, it took the federal government 40 years to figure out how to measure blood pressure. And finally in NHANES III, it was done correctly. And in addition to that, I think we've now come to a final resting point about how to do it using automatic machines and have a person in a room without an observer. So then, so now I think there's a potential to actually go out and try to get standardized blood pressures, but I don't think we really have any good data about the distribution of blood pressure and hypertension risk across Sub-Saharan Africa. I think that's a very important question. And one of the things we should do in the United States now, I think it's a challenge to figure out ways to track blood pressure over time too, because that's another dimension that's completely missing from this study. Sure. You've quite convinced me that the genetics of blood pressure is nothing compared to the effect of the environment. Are there any other things that you've discovered where the environment is, you know, would change your mind about what you think about the genetics? I know blood pressure is relatively easy to get and there's a lot of data about it, but there should be other things too, don't you think? Well, first of all, I've been very careful throughout my career not to claim that we have demonstrated that genetic effects do not exist or we can't rule them out. We simply don't have the information to do a definitive test of that question. And the other issue I think of this problem plays out across most other non-communicable diseases, chronic conditions, I mean, certainly for obesity and diabetes, it plays out in the same way. And we saw a story that was told that first it was a Pima Indians that were predisposed, then it was Black Americans, then it was Asians and the highest rates in the world now are in Saudi Arabia and of course in Europe, people were gaining weight. So you saw it unfold in a way that undermined the integrity of that particular argument that you could isolate people with a thrifty genotype who are more likely to be predisposed. I think that's been kind of an instructive example for people to grapple with. Where we had a very strongly specifically formulated genetic hypothesis that the South Sea Islanders were selected for being, have a thrifty genotype, more efficient use of calories that they consumed. And that clearly is not the case. There's nothing special about them. They just got there first, unfortunately. All right, thank you very much.