8. Demystifying Genetics with Paldeep Atwal, M.D.

Episodes have been transcribed to improve the accessibility of this information. Our best attempts have been made to ensure accuracy,  however, if you discover a possible error please notify us at info@bendybodies.org

00:00:00 

Linda Bluestein 

Welcome to bendy bodies with the hypermobility MD. This is your host, Dr. Linda Bluestein here with Dr.  Paldeep Atwal board certified clinical and medical biochemical geneticist, and director of Atwal clinic for  genomic and personalized medicine. He completed his genetics fellowship at Stanford university and  subspecialty biochemical genetics fellowship at Baylor college of medicine. Before serving as medical director  for the individualized medicine clinic at Mayo clinic in Florida, he has a longstanding interest in rare and  undiagnosed disease, including the use of multiple concurrent genomics platforms to provide a diagnosis to  patients. He conducts translational research with the goal of discovering new genetic syndromes and designing  new therapies for genetic disease through his work. He co-led the discovery of by parental mitochondrial  inheritance in humans discovered two new genetic connective tissue syndromes. Co-developed an un-targeted  metabolic screening test for inborn errors of metabolism and published extensively on human genetics with over  70 peer reviewed publications to date.  

00:01:02 

Linda Bluestein 

In this episode of bendy bodies, Dr. Atwal and I chatted about the genetic influencers of joint mobility and  possible explanations for why all bendy people are not alike. Other topics covered, include how epigenetics are  more like an accelerator pedal than a light switch and how dietary modifications may influence DNA repair,  especially amongst those with obesity, diabetes, and or cardiovascular disease.  

00:01:43 

Linda Bluestein 

Dr. Atwal thank you so much for joining me today on bendy bodies. Let's start out by talking about the  incidence of hyper-mobility disorders. I would like to know, compared to the general population dancers and  other flexibility artists like gymnast, they're known to have a higher incidence of hypermobility and hyper-mobility disorders, which is the umbrella term that we use to describe people with symptoms related to joint  hypermobility. Can you start out by telling us about the different genetic and non-genetic reasons why someone  might bendy, which is the term we use to describe people who have a greater than average range of motion?  Yeah.  

00:02:43 

Paldeep Atwal 

Yeah. I think we can talk about a couple of different things there. The first thing is non genetics, just in general,  if you think about a population of people there's variation in that population. There's an average level of  flexibility or mindedness, and that tends to follow what we call this bell shaped curve or normal distribution.  Some, most people will be in the middle of that. So there's some that will be really inflexible. They'll be really  stiff and it will, some people are really flexible and that's just a normal variation in a population. Now there are things that influenced that even in those populations, for example, there's differences between males and  females. On average males tend to be less flexible than females on average. Some males that are more flexible  with females of course, and there's reasons for that as well. Things like still in an underlying, differences. That's  a higher, that's a more kind of population higher level, and then we get into the genetics of things. If you think  about two types of genetics, there's single genetics are Mundelien after Gregor Mendel, and then there's complex  genetics. The really talk about interactions between multiple different genes together that may influence a  second trait. Single gene is on the we're most familiar method and work with the most. And, when it comes to  the practice of clinical genetics and medicine, and we know that there are genes that influence that.  

00:04:15 

Paldeep Atwal 

For example, the Ehlers-Danlos genes that Marfan and other what we call heritable disorders of connective  tissue. These are genes that work on that are involved in the structural proteins and the connectors and the  connective tissue, the collisions, the fibrillin, and changes on their input and influence how tightly those  colleges, et cetera, bone together, and that can translate to joint laxity. The other part of that is there might be  small changes and a number of genes, let's say 50 genes, a hundred genes. If there, all of those genes are  changed and a Sarah and wait, now we're talking about complex genetics, complex traits, then you get, that  influence of their trait, whether the, in this case flexibility. Let's say there's a hundred genes that for example,  there's looked at as a hundred genes that are involved in high school, you are planting those a hundred, all have a stair and the change in one way, I'll make you more flexible.  

00:05:17 

Paldeep Atwal 

Whereas having another way might make you less flexible at each. Gene has tiny amount of influence, but on  aggregate that's what they're skewed, if that makes sense. That's one of theories behind hypermobility disorders,  perhaps it's not a single gene and perhaps it's a complex trait that has multiple genes involved. So anyway, I'll  stop there. That's a, that's a lot so happy to talk more about this,  

00:05:47 

Linda Bluestein 

That that really is a very helpful explanation though, because I think that when I spoke to you before for the  hypermobility happy hour podcast, and you were explaining about phenotypic versus typic expression, and, that  really helped me to understand why there's so many people that may look like they have, a variant of Ehlers Danlos syndrome, which we know is the more common, heritable disorder of connective tissue. Right. They  may be don't because of what you're explaining now, in terms of this complex, genetics that maybe it's not a  single gene, but a whole host of genes interacting together, if I'm understanding you correctly, right?  

00:06:30 

Paldeep Atwal 

Yes, exactly. Exactly. Yeah. If you think about genetics we have in humans, we have 20,000 genes. It's not,  that's not a big step to suggest that those other genes interact with that gene that might be causing a particular  condition in some way, such that even if you see it in families all the time, we call it beer variable expression.  That if they all have, if there's a condition that runs in the family, let's see siblings or our parent and child, they  might manifest condition differently. One may be more severe than the other, but one might be less severe, et  cetera. The question then is, well, why is that the case? If they both have the exact same genetic change in that  gene and its other influencers, all of that, how does that manifest? So other genes, other, there's other  mechanisms such as epigenetics, which I think we might talk about later. 

00:07:32 

Paldeep Atwal 

It's not, it's, everything's working with each other, it's like a big melting pot and it's not, we like to think of it all  separate, but it's much more interlinked and connected then some people like to think of it, let's say. 

00:07:46 

Linda Bluestein 

Sure, sure. Can also help us to understand why were people that you see people that I see that, clearly have some  hyper-mobility disorder, but so they have similarities, but yet they look, they can look so different from each  other, even within a family. Yeah exactly. So so let's talk about epigenetics actually. Let's just jump right into  that. Can you explain to us what epigenetics is, how that might influence genetic expression and how people  who are bendy can use or people who aren't, but in general, just how can we use that to our advantage?  

00:08:24 

Paldeep Atwal 

Yeah. Yeah. So let's talk about everything. I think genetics has, one of the main mechanisms to control gene  expression. The concept of gene expression is the idea that you have genes like textbooks or recipes, and  sometimes you'll be using them. Sometimes you want to be, and also sometimes you will be using them a lot.  Some things you'll be using them just and the way the body controls, how much it's using them, or if it's using  them at all as control mechanisms like epigenetics. It's a way to control the expression or the functionality of a  gene. People think of epigenetics, like a light switch that switches the genome, or as soon as and that's it, there's  like a binary function offer on, where does in reality it's more complicated like that. They're not, it's more, it's  better to think of it like an accelerator pedal and that a gene can be cruising along a theory.  

00:09:35 

Paldeep Atwal 

You can put it, you can go to up to 50 or you can really sit down and have to look a maximal expression of that  gene and epigenetics is the way that is controlled. Does that, does that make sense?  

00:09:51 

Linda Bluestein 

Yes, it does. That does make sense. I like the idea of, rather than the light switch, the accelerator pedal, because  we know that in terms of nutrition and exercise, and these are a couple of things that influence.  

00:10:04 

Paldeep Atwal 

Exactly. That was where I was just going to go into. Thanks for that. So, so then, to answer your second part of  your question, how do we optimize things for bendy people. We know that there's a number of things that  influence our gene expression exercise. You mentioned exercise, you mentioned nutrition. These are both is that  we can quite significantly influence our epigenetic expression, epigenetic control mechanisms. If we, do the  right things from an instructional perspective, and, exercise, and a conditioning perspective that influences the  DNA in our body, which is an amazing thing to think about. People may not realize it has such a profound  effect, but that's truly what's happening. That's why you're seeing you see the changes, in the weeks or months,  or from making these kinds of changes in nutrition or exercise, it's truly causing a change in your DNA  expression, which is,  

00:11:20 

Linda Bluestein 

Yeah, that really is amazing. I think that a lot of people get very frustrated because they'll read the headlines of  different studies and they'll say, Oh, but people keep flip-flopping on nutrition and what we should be doing. If  you really think, if you really look at the big picture, most of the messages have stayed very consistent over the  years, avoid sugar and white flour. We want lots of polyphenols and, plants in general are good. So, so, I think  that part of the difficulty, if understanding this correctly is that yes, nutrition matters greatly and affects our  

DNA, but it's just a hard thing to study. It's hard to conduct those studies and to really be able to demonstrate  correlations because of the, humans don't remember super well. Like I can't remember what I had to eat  necessarily yesterday much less for the past five years and, 

00:12:13 

Paldeep Atwal 

Right, right. Let's talk about nutrition for a minute. There's well, firstly, there's a lot of misinformation out there  and that is unfortunate to your point, highly processed foods that all of the micronutrients and Everett is pulled  out and it's, the end result of a sugar load that tastes good very quickly. It doesn't really tell you, it doesn't  actually provide you any nutritional value. The first thing to do to separate calorific value or calorific content  and nutritional value or nutritional content. You look at food, you should look at the balance between nutritional  use and calorific use now. In the past, when, before this realization before refer to sound like, well, before  refrigeration, there was a calorific deficit, and that humans experience us that it was actually hard to find enough  food, right. That 15 to 1500 to 2000 calories a day was a challenge. Certainly in the US, we have no such  challenge at all.  

00:13:27 

Linda Bluestein 

Right. You can find that one meal, no problem. So, so, but we have a genetic programming that still craves  highly, calorie dense foods, right. We have to kind of overcome that and really focus on the nutritional aspect of  those foods rather than the calorific density. We really actually don't need calorific density in our food because  we have so much food available. We should w we should actually even limit the calorific density and focus on  nutritional density. And that's more relaxed. They get more full with that. There's a, there's also a great study in  this comment recently, and you may have been following this. I've certainly been following it. There were some  literature and documentation of things like intermittent fasting, and, people like all these different types of diets  that ketogenic diet and all of that. Now that to your point on people are able to track certain, Google are able to  track w how are they getting what they're think when reading with apps and things that there's a bit more  awareness.  

00:14:42 

Paldeep Atwal 

I think, there was some, there's all this fad diets and some crazies that come and go. I think, and it's the, I don't  think it sound, I don't think it's the answer, but I think that a lot of people have this beneficial effect with it on a  short term, because it's probably the first time they've been out of glycolysis in their lives. Are they concerned  

that they can remember it and that they're using, they're not using good glucose or stored glucose in the form of  glycogen as their primary source of fuel. They're switching to fatty acid oxidation, which is, if you think about it  the maximum time they, if someone wakes up, they have a cereal or some other thing with lots of carbohydrates,  then they have lunch a few hours later, then they get home, they might have a snack, then they have dinner.  

00:15:39 

Paldeep Atwal 

They might have a snack before bed. They're never really have a time where they are not getting a carbohydrate  intake. When they are, they've got plenty of black to ensure they're never really need to go. That's really the  that's really why people notice such an effect with it. But there's a great review article. Couple of months ago, it  came out in the new England journal on intermittent fasting and its role in health and an aging. It really looked  at that switching between the glycolysis and fatty acid oxidation as the true benefit and terms of expression of,  DNA repair type, our DNA protection type of molecules, all of these types of things. It's a great paper. I would  encourage everyone to read it, even though it's very medical.  

00:16:37 

Linda Bluestein 

And, and I'm sure there's some people who are going to go, wow, I've tried the intermittent fasting. I've tried the  ketogenic diet. I and I definitely have noticed some improvement, but there's going to be some words in there  that they're going to say, Oh, I don't know what some of these things mean. If if in my view, what I'm thinking  of is, when I talk to my patients about, that they say, Oh, I have such a sweet tooth. I just, I, I crave sugar and  stuff like that. It seems like once you switch to this, a way of eating where you're eliminating a lot of  carbohydrates and you're focusing on, like you said, nutrient density and also having periods of time that you're  not eating the intermittent fasting. If you're going 12 hours without eating, or, depending on the guidelines, 12,  14, whatever hours without eating, just drinking water and maybe have some green tea or something, but you're  not consuming anything that's going to, nothing with calories, right. 

00:17:37 

Linda Bluestein 

That that I think it seems like that really helps to minimize yeah. Those cravings.  

00:17:45 

Paldeep Atwal 

It does. One of the biggest things people need to do is be aware of how they're feeling and why they're feeling it  often. The first thing is they're actually requiring more water intake when they feel hunger. Seeing what a glass  of water does for their hunger levels. The second thing is it's interesting to know that, and I, I feel this as well,  actually as your hungriest when you're eating, which is pretty interesting. You start eating is when you're  actually become the most hungry and you want to eat more the most rather than when you're, you go on five  hours without a meal, which is, which doesn't make sense when you think about it, like offensively. It really is  the case for many people.  

00:18:33 

Linda Bluestein 

That is very interesting. Huh. That is very interesting. To me, when you really think about how pro inflammatory sugar is and how many conditions that we have are so related to inflammation that, to break that  cycle of the sugar carbohydrate, cravings is so important, can make such a significant difference for people.  

00:18:59 

Paldeep Atwal 

Yeah, absolutely. Yeah absolutely. I agree. I agree.  

00:19:02 

Linda Bluestein 

So, so can you tell us about why the prevalence of hyper-mobility disorders, seems so much greater in females  than males?  

00:19:11 

Paldeep Atwal 

Yeah, it's very interesting. I think the way I think about that, and we have to explain it's back to this, population  norms and the bell-shaped curves. I mean, think about the, one of the prime manifestations of, well, let me just  say that when you say that the prevalence of hypermobility or let's talk about the preference of hypermobile  EDS, so just EDS in general, when it comes to the, hypermobile type, the manifestation, primarily as on house,  as hypermobility, right? first the first thing that people notice, or maybe don't notice it's always there, if you  think about those populations of males and the population of males and females, men on average are less  flexible. They're on average, not as bendy as women, just the differences in hormones, primarily differences in  testosterone level. Now to compound that, and it's important to realize it has a compound effect because of the  difference also in level men, all men on average have more lean muscle mass than a woman.  

00:20:33 

Paldeep Atwal 

If you think about the second, most common thing pain, right? So you get loose joints because the muscles are  having to work harder to support those loose joints. You get this manifestation of pain and fatigue. Now if  you're less flexible and we have more muscle mass to support those joints, you are going to manifest less, which  is also some of the ways we treat it right. We encourage people to increase their physical conditioning. That for  me is the reason that men seem to manifest less than women it's purely, well, it's not purely, but a big  contributor certainly is this hormonal difference between men and women. It causes less flexibility and more  lean muscle mass.  

00:21:20 

Linda Bluestein 

Sure. That would fit too with the onset of menstrual cycles in females being often a time where they start to  have more problems with their, when they're, less than 10 or whatever course now, since young ladies are  starting to often have their periods at a younger age, but, they are there, especially when it comes to something  like dance they're bendy, and that it's actually seen as an advantage. They start to get their menstrual periods and  they start to have that's when they start to have pain. I'm always surprised at the patients that, started having quite a bit of pain at a relatively, young age. If you ask them, when did you start your periods? And that's often  seems to correlate with that,  

00:22:05 

Paldeep Atwal 

Right? Yeah. It's a great point there. That's the hormonal influence is definitely there and both ways. Sure.  

00:22:16 

Linda Bluestein 

In terms of genetic testing for people with, joint hypermobility, what types of genetic testing would, do you  think is important to consider and, when would you say that's indicated?  

00:22:29 

Paldeep Atwal 

Yeah, so I think for someone who is presenting with a possible genetic or genetic condition, or how, or heritable  disorder of connected to most of the time genetic testing is appropriate, and that it used to be very challenging,  very expensive, very hard to do genetic testing nowadays, to do a large gene panel or even a genome sequence,  an exome sequence shortly, probably genome sequence. That's not, it's not that challenging anymore. There's  insurance coverage for these things. There's a, multiple labs that are competing with each other, trying to drive  down price, drive down, difficulty in access and get more patient friendly reports and, more availability of  counseling and interpretation services. I think the option for anyone with presenting with one of these should be  there now, whether it's a strong option or strong recommendation depends on their symptoms. If someone  clearly has, symptoms suggestive of a prototype or, severe subtype, like a, or a lot of them also think they  should be strongly recommended, they get the testing.  

00:24:02 

Paldeep Atwal 

If someone is, let's say perhaps a bit later in life has kind of self select against having one of the severe forms  and hasn't had any issues has a number. It has all of the features consistent with perhaps the hacker mobile. It's  less of a concern to do the testing. I will tend to offer it to people as a reassurance to them, if they would like to  do the testing, I believe strongly advocate, people should have the option to test that we want. There's a personal  utility to that. The, the clinical utility may not be as high as the other scenario, but certainly there is a clinical  utility as well. So, so broader testing is the way, if you look at what's happening in medicine, it's broader testing,  more, awareness of the subtle differences. The trend is only increasing in that direction.  

00:25:06 

Linda Bluestein 

And, and I actually had a patient that I just did whole genome sequencing. I had ordered whole genome  sequencing on, the other day. I was so happy that the insurance company did approve it and that the report came  back in a very, for non geneticist, a very user friendly way. It was and the patient was very, felt very validated  and everything. It's, I think it's such a helpful thing. If I understand this correctly, it used to be even quite  recently that we only had, really in terms of like, if you wanted to use your insurance a very limited panel that  you could maybe even get approved, and it would often come back negative because, you're having to target a  very narrow focus. Whereas now we're able to look at a much broader picture and in many cases, not always,  but in many cases, look at a broader picture and get a lot more information.  

00:26:04 

Linda Bluestein 

It's much more genetic testing that you could do now as much more useful than what you could do even five  years ago. Am I understanding that correctly?  

00:26:14 

Paldeep Atwal 

Yes. Yeah absolutely. Absolutely. That's exactly the point I was trying to make. So thanks. Thanks for, thanks  for that.  

00:26:21 

Linda Bluestein 

Okay. Okay. Good. It comes to, Ehlers-Danlos syndromes specifically, we know that multiple different types  have been identified and that we know genetic markers for all, but the hypervariable type, which we also know is by far the most common type, how much progress has been made on finding the markers for hypermobile  EDS. Can you just explain, I know we've covered this but, why is processes so challenging? 

00:26:44 

Paldeep Atwal 

Yeah. I think in that sense, I think the progress is a binary function and that we find a gene and then there's  progress and tell we defined it in, there was no progress, but there's more to that. So I'm not being fair. The let's  start, what's being done well, there's lots of different groups that are getting cohorts of individuals together as a  hat hacker, mobile IDs are doing genome sequencing and other methods to try and identify some commonality  and their genetics. That would be a marker or a gene that would bending it. Lots of people have done that and  that's not really worked. I'm not sure that's the, I think that's very valuable, data, for a number of reasons, but I'm  less convinced. Well, let me tell you what to me, I think the possibilities are, number one, and it's not a, type of  genetic change that is readily testable by current sequencing methodology.  

00:28:08 

Paldeep Atwal 

I don't want to get too technical here, but currently virtually all testing is done on what's called a massively  parallel, short lead sequencing platform. People call it next generation sequencing, but I don't like that term  because I don't think it's very accurate. It doesn't tell you what touch, what happening. It's imagine the gene is  broken up into thousands of tiny little hundred base pair, or 75 to 150 base spirit strands. They're all sequenced  and they're all stuck back to begin by computer. That's how you figure out what the sequence is. No the problem  with that is it's not good at testing for certain types of genetic changes, certain sizes of deletion and genie,  certain structural rearrangements, insertion deletions, complex rearrangements. All the information right might  be there, but it's not in the normal place. It's actually not very good at detecting those types of changes.  

00:29:14 

Paldeep Atwal 

The other nearest sequencing technology is long read sequencing technologies that are better at that. I think  employing some of those technologies, when we're looking at these, patients to try and find, is there some  structural abnormality there that's one number two, it's a post genetic change as opposed to, and so it's not a  DNA level change. It's an RNA, a post-translational change, or it's an epigenetic modifier, right? As we talked  about, that's primarily driving this, but that needs to, we need to look at different things for that proteomics and  metabolomics and, epigenetic, methylation type things and the methylome. The third thing is it's not a single  gene that's causing it back to the earlier point of the complex kids. There's multiple genes that are involved in  there's some threshold type of fat that's causing it. That's much harder with current level of technology we're at  that.  

00:30:25 

Paldeep Atwal 

The idea is that there's, once you get a certain amount of changes, you would get this kind of threshold point or  crossover point where you'd manifest the condition. That's idea, but then this complex place, there are, there's  progress in that, in terms of using things like polygenic risk scores to make determinate emanation of risk of  things like coronary artery, disease, diabetes, et cetera. There is a lot of progress there, but that hasn't really been  applied to things like, re rare genetic diseases, more common diseases that have a small genetic component. We  do think it is genetic. It does clearly runs in families. It clearly has overlapped with other well-defined genetic  conditions. Now, I do think it's genetic, but that, those are the reasons I, I think there's a gene has not been  identified yet.  

00:31:31 

Linda Bluestein 

Sure. It's much more complicated than what meets the eye. I mean, I think a lot of the information that has been  presented to us, is, if they don't meet these new super strict criteria for hypermobile EDS, then therefore is HSD.  Yeah.  

00:31:52 

Paldeep Atwal 

Yeah. I mean, I think we have to realize consensus expert opinion for what it is, and I don't know, I think it's  highly valuable, highly useful, and I think we should be using it, but I also realize, wanting to make the point  that consensus expert opinion is not a substitute for robust molecular science. Right. So, so what I mean by that  is once we find a gene for something, whether a consensus of experts thinks someone has it or not, it becomes secondary to whether they have a pathogenic beer and that genie that perhaps is an expansion that phenotype, or,  it's still valuable, but it's, but there's a higher level of evidence now with the molecular findings.  

00:32:49 

Linda Bluestein 

That, that makes sense. Yeah. And, and I know I just threw out the HSD and some people might not know what  that is, but, so real quickly would you, cause I there's several things that I want to make sure that we can cover  yet. Are you willing to just maybe give more of an explanation about the consensus, criteria for hypermobile  EDS and, when in 2017, when they introduced this category of hypermobility spectrum disorder, is it possible  for you to give just a few sentences on kind of the significance of that?  

00:33:26 

Paldeep Atwal 

Yeah. There was a change from before and to, in terms of that, the criteria diagnostic criteria for hypermobile  Ehlers-Danlos syndrome, it's now part of, as part of this hacker and Belky spectrum disorders, and this  represents the kind of severe end of it. To meet the criteria for the hyper mobile EDS, there's a number of  criteria and three major ones generalized John hacker mobility. Then, the second criteria is there's two or more  of, features such as, soft developed skin pathogenic pop pills or recurrent abdominal hernia is just an example.  Post a family history is at a separate one and also separate as, muscle-skeletal pain and two or more lemons  daily for at least a few months. And then the third major criteria. As the absence of a clear, other explanation,  like, rheumatoid arthritis, or absence of a clear neuromuscular disorder, they would cause these beans or Marfan  syndrome or, our absence of unusual skin or fragility suggestive of another type of BDS.  

00:34:42 

Paldeep Atwal 

More of the, more of a exclusion criteria, make sure you're not missing something else. It's quite the idea with, if  you look at it's a one page form. To me, the idea is someone who doesn't have that much awareness of Ehlers Danlos, if it's useful for that person to help them feel comfortable and making a diagnosis. It's intentionally kind  of, specific and restrictive, but remember, we're talking about complex genetic multiorgan condition. That's been  condensed down into tick boxes one page, right? So we just have to realize that's what that's, what's happening  here. There's obviously going to be major limitations, but something with doing anything like that,  

00:35:29 

Linda Bluestein 

That, that's a great explanation. I, I also want to make sure to talk about, especially since this podcast is very  much focused for, people who are bendy, but, might be doing things like dance and other, athletic and artistic  endeavors. There was a really fascinating article published recently that, the title was high prevalence of  connective tissue, gene variants, and professional ballet looking at, a group of dancers at the Houston ballet. I  was curious if you could comment on that study and its potential significance for other bendy dancers.  

00:36:11 

Paldeep Atwal 

Yeah. I am not that familiar with the, that study in particular, but I'm happy to just talk about it in general.  Studies like this, it looks at, it's there by design, they're useful in that they look at population and they analyze  features of that population and make an fares conclusions based on differences in that general population. So  very useful. What they w this one, I, I, I haven't read the study in detail, but I've, I gleaned over the abstract.  They looked at increased, they find increased prevalence of variants and no one can irritate your genes and that  in this population over and above the general population, I think that is interesting. That there's, it suggests that  there's some gene interaction or some con more complex interplay between these genes that is causing  something, which fits with one of the things I said earlier on complex traits. 

00:37:29 

Paldeep Atwal 

I think there's a lot more than they used to be done here. The one question I would have in this particular study  as these are variants compared to the general population, but are they known to be diseased cause appearance or  are they just rare variants? If that makes sense, like uncommon genetic variants that aren't necessarily known to  cause disease themselves, but are different to the normal genetic bear in there. I think it is that, but, which makes  sense, it's more of a suggested, there's a gene interaction effect going on in these kind of gene clusters that there  changes and a collection of these genes cause something perhaps hacker mobility. It really actually speaks to the  point on comp gene interactions causing hypermobility. 

00:38:28 

Linda Bluestein 

In terms of other types of genetic testing that can be done like Foco, genomic and other snip testing, single  nucleotide polymorphisms. We know that's quite popular right now, shifting gears for a minute. What should  people in general know about that type of testing?  

00:38:48 

Paldeep Atwal 

Yeah, so I'm a big advocate for pharmacogenetic testing. Let me just explain pharmacogenetic testing. It's  pharmacogenetics is the science of how genetic variations and your body influence how you metabolize drugs.  That's the kind of ones the one-liner. It's, surprising to some people are on surprising to others that just since  your genetics influences so many other things like your hair color, I told you are, and I call it all sorts of other  things. When you take, when you take a medication will influence how you respond to that medication. This  science, this is not a new science it's decades old, but, the clinical use and clinical application that has also not to  that new, but it's certainly near than the knowledge of it. Nowadays what people do is if you have a baseline  profile of your pharmacogenetics, ideally before your need to be on any medication I went up and when you  need to be on a medication, you, whether number one, that medication is going to be right for you are going to  work for you.  

00:40:00 

Paldeep Atwal 

Number two, the standard dose that has given to, a 30 year old bodybuilder or a 90 year old lady that weighs 90  pounds or so, which was also an interesting side topic. That the right dose for you? or as it, or do you need to  have an increased dose or decreased dose based on your genetics. A common example, Plavix is an anti-platelet  medication taken for heart attack and stroke. So millions of people around the U S. There is, FDA black box  warning label on the label of that's drug that suggest that says that pharmacogenomic variants and, second CYP  enzyme in the liver influence how well you metabolize this drug such that it may not be effective for you. It's  recommended you have, that these spirits are looked at that's the FDA black box warning label. That's says it's  not, the side note or anything, Boston, majority of people are on Plavix. I've never had their enzyme. It's the  CYP two C 19 enzyme. They've never had a check. So they're on Plavix. Hopefully it's working for them, but  we know that up to a third of the patient have variance in that gene, that it doesn't work for them. That makes  that gee, wow. It doesn't work. Just imagine how many people that might be that are on Plavix that may not be  metabolizing it the way they should be.  

00:41:47 

Paldeep Atwal 

It's kind of scary.  

00:41:50 

Linda Bluestein 

That that's mind boggling. If I'm understanding you correctly, there's a drug that's being commonly used called  Plavix that is being used on millions of people. There's a known pharmaco genetic variant that is prevalent in  like a third of the population. Very large percentage of people that would be ability to do multiple variants,  excuse me, but we have the ability to test for that. Most people have not had that kind of testing. They might be  taking this drug for most of the recommendations, following, stent placement or whatever it might be for a year  or even longer. And it's a potent drug. There are certain implications when it comes to, if they need to have  surgery or, something else and taking them off of the drug. And so, wow, that's, that is,  

00:42:39 

Paldeep Atwal 

Just to add to the point that you've made there, you talked about stamps and obviously one of the biggest risks  with having a standard STEM from bosses, the studies have been done showing that people who have non functional pharmacokinetic gerunds and the CIPC 19 variants are significantly increased risk of stent  thrombosis. If they don't have to put on Plavix, because Plavix doesn't have the ante for the effect that they're  needing to prevent it, studies are right there. They're done, but it's still not commonly tested. It's a real shame.  

00:43:18 

Linda Bluestein 

Are you saying if I, I just wanna make sure I'm hearing you like, so are you saying that if you have that genetic variant and then you get put on Plavix, your risk might actually increase if as if you were not on Plavix  thrombosis?  

00:43:32 

Paldeep Atwal 

No, no. Your best reduction of stent thrombosis being on Plavix is not right. So yeah. You should be put on  something else that causes the effect. That of that was the point. Yeah. The risk reduction of that drug, that  you're, one for, second heart attack or two for stint and fit stands, and bosses that your hope you're hoping to get  by taking that pill every morning. You're not getting it. That's sorry. That was the point I was making.  

00:44:05 

Linda Bluestein 

Sure. No that makes sense. Really what it seems to me that pretty much it, any of us that could afford to have  this testing done. I know sometimes it is covered by insurance and sometimes it's not, but that type of testing, it  seems like it would make sense for most of us to have that.  

00:44:27 

Paldeep Atwal 

Yeah. Yeah. I think it should, I, the way I think will go, I don't know, way in five years, 10 years from now, it  will be a population level thing that is hopefully the norm where it's part of the prescribing decision-making,  well, let's prescribe this drug well, let's make sure it works for this. It's personalized, it's personalized medicine.  We're getting into your precision medicine, right. It's the right drug for the right patient at the right time. It the  right drug that doesn't match up with their prompt with genetics or doesn't need to be this other drug? And so  that's hopefully where we get to, but, things, in healthcare, things tend to move fairly slowly.  

00:45:13 

Linda Bluestein 

Sure, sure. That's a perfect lead into, to the last topic that I wanted to cover, where things are not moving.  Slowly, and that's what the coronavirus pandemic, and, this has happened, quite quickly actually. We know that  there are a number of people who have had, some of this, a single nucleotide polymorphism, testing, other types  of genetic testing. I'm wondering if, we see these reports about, it's mostly the elderly that are getting very ill  and, or, dying, but that sometimes we see, young, healthy people, that have become very ill. I'm wondering if, is  this possibly related to some kind of genetic variant that causes them, to be at much higher risk of  complications, especially in regards to cytokine storm, is there some explanation there potentially,  

00:46:12 

Paldeep Atwal 

Certainly there, if you think about all of the cytokine storm, all of the immune system on the underlying, all of  that, there's a there's genetics that decides how your immune system functions. To answer the question as there a  genetic influence, that response, that influences how your body responds to a viral illness. Absolutely. And we  know that's there. We know we actually can see it on a much simpler level. If we look at even differences  between men and women coming back to that, again, it's such an easy example. We know that because of the X  chromosome differences and women such that sail has either one X-chromosome on or the other. Women are,  really a mosaic of two X chromosomes, that those, that changes the immune system and that it's more diverse  now, which is a good thing to fight infection. Actually, I, and I, neonatal intensive care unit, female infants  actually do slight on average, just slightly better than male infants.  

00:47:33 

Paldeep Atwal 

One of the reasons is because they're more diverse, they're thus more adaptive immune system. It's a small, it's  not big difference, very small difference. Secondly, we know that, women on average tend to have more  autoimmune diseases. That, and this other way, right? So it's too much different, right? So we can apply all of  those things to this as well. Of course, there's going to be differences as someone who is a sensitively health and  doesn't have an obvious problem. They might have some genetic modifier that increases their risk. That's not  something practically we can do anything about it right now. We can only focus on that. I would tell people to  focus on the things you can do during your health is the best it can be. Your immune system is as strong as it can be. You did touch on that trust and paper on the cytokine storm. 

00:48:30 

Paldeep Atwal 

And, that really seems to cause a rapid deterioration and the status of individuals. I think looking at where it's  happening in the long run, if you think about the purpose of, well, what, a cytokine storm, it's a pool,  inflammatory response to, combat the pathogen in this case, right? The problem is it can get to the stage where  it's almost like what's the difference between a sniper is building and a carpet bombing. ? Right So it's very  precise. One is very precise and one just, okay, it gets rid of the thing you're trying to get rid of, but it  unfortunately gets rid of everything else. If this is happening in the lung, it's a massive fight storm. You're  getting destruction of lung tissue and destruction of all the normal gas exchange that you're going to be needing  that can actually cause more problems and benefits. And, this is more your ear to the main, I think, when, so I'll  defer to you on expanding some more of that.  

00:49:48 

Linda Bluestein 

Yeah, no, it's a fascinating area. I know you and I are also involved in some groups that are very actively  involved in discussions about, what potential, things could be used. Unfortunately there's not as much science  there is as, a lot of us would like, but there's enough information that, certainly for myself, I know that I have,  made a lot of changes to my, kind of the supplements that I've, that have been taking, to try to, make my  immune system is as robust as possible. The genetic component of that is also very interesting, Okay. Well, very  good. There anything else that you would like to add and can you let us know where people can find you?  

00:50:34 

Paldeep Atwal 

Oh, sure. Yeah. I, so I have a clinic that's based in Florida, North Florida, Jacksonville. Normally I see people in  person as well as remotely, but right now I think it's virtually all remote. I'm able to do telemedicine  consultations for genetic consultations, for Ehlers-Danlos and other genetic conditions. A website is  atwalclinic.com. You cancall them, there's a email address. People have inquiries on certain things and,  otherwise, there's a, we have a blog as well. Then we, I love education like this. I, I think I've done one of these  with you, for Linda as well. We, I hope you invite me back as well, but I love education. I love spreading the  right information and making sure people are informed and able to make their own decisions and how that help  best manage their care going forward.  

00:51:37 

Linda Bluestein 

Fabulous. Can patients see you from a wide variety of States or do they have to be in the state of Florida? How  does that work?  

00:51:44 

Paldeep Atwal 

Okay. I have licensure and multiple states and obviously it's state licensure dependent. There's one good thing  that comes up with all of the, this whole, this horrible, situation were done with coronavirus. I think it's  understanding the power of Tallyman and why we need big change and how telemedicine is practiced in the U S  I completely disagree with this idea that every state as should, you have to get licensure in every single state to,  there needs to be a federal medical license, right. Or something or something that our federal telemedicine  license or something like that, it can help. Anyway, I'm asking, and I realize I'm perhaps asking for too much,  but yes, the answer, your question is restricted. It's restricted based on the state. I had to, I've got to have  licensure in multiple States. I don't want to say which States, because that my diet is changing and that continues  to change as I either ramp up or up then some of that.  

00:52:49 

Paldeep Atwal 

Yes, the best thing would be for them to just ask, and we can clarify, or they can, or we can use, look, find,  spend some way to make it work, whether in person or some other way.  

00:53:05 

Linda Bluestein 

Okay. Well I, I could not agree with you more about the, hopes that I have in terms of making some real  changes, because we, up until now have been really asking the sickest patients to travel the most distance, to see  people that really could help them. A lot can be done via telemedicine and, you and I participate in some groupsthat do some collaboration and some, consultations that can benefit patients. It needs to be, I think, a lot broader  so that we can help as many people as possible. Well, it was so fantastic speaking with you and I am so grateful,  for you, coming on bendy bodies today. Well you all have been listening to bendy bodies with the hypermobility  

MD today. Our guest has been Dr. Paldeep Atwal board certified clinical and medical biochemical geneticist,  and director of the Atwal clinic for genomic and personalized medicine.  

00:54:09 

Linda Bluestein 

Dr. Atwal. Thank you so very much for taking the time to share your knowledge with us today.  

00:54:14 

Linda Bluestein 

Please go to bendybodies.org for links to all the episodes and to access the show notes. If you enjoyed this  podcast, please share, leave a review and consider rating us five stars. Don't forget to subscribe. You will be  notified of all new episodes. Feedback is greatly appreciated and can be emailed to bendy bodies  podcast@gmail.com. Go to hypermobilitymd.com to sign up for my newsletter. Thank you to Rhett Guild for  production and sound editing to Andrew Savino for composing original music and to Jennifer Arsenalt for  designing the bendy bodies website and cover artwork. This podcast is for informational purposes only, and is  not a substitute for medical advice. Please see your own medical team prior to making any changes to your  health care. Thanks for tuning in, and we'll see you next time on bendy bodies with the hypermobility MD.