Episode 71: Understanding Your Risk with a PRS
Karie Dozer [00:00:03] I'm Karie Dozer and this is TGen Talks. Let's think about our genetic risk for certain diseases in simple terms, like a card game. We are all dealt a hand of cards, and we have only those cards to use to win or lose the game. What if your physician could deal you a hand of cards that numerically represents your genetic variations, thus your chances of getting a certain disease or being protected from a disease compared to others. A simple test to determine your polygenic risk score considers many variations to estimate your overall risk of disease based solely on your genes. Unlike a family history, which can be inaccurate or incomplete, this information is clinical and can help you and your doctor make informed decisions about how to best live a long and healthy life. You're about to hear from an associate professor in the Quantitative Medicine and Systems Biology division at TGen. About just such a test. Whether you're a health care professional, a genetics enthusiast, or you're just curious about the future of personalized medicine and how it can help you. This 20-minute episode is worth the listen here. To talk a little bit more about personalized health care is Doctor David Duggan. Doctor Duggan, thanks for taking the time today.
Dr. David Duggan [00:01:19] Yeah. My pleasure.
Karie Dozer [00:01:20] Tell me a little bit about what you do here at TGen.
Dr. David Duggan [00:01:22] Yeah. So at TGen, my research, translational research really focuses on identifying genetic changes that we're born with, that we can then use to predict, future diseases, and hopefully prevent that, before those diseases set in or at least detected early.
Karie Dozer [00:01:39] Most people who aren't in health care and don't know a ton about genomics, what you're talking about, what you're describing is exactly what's so exciting about genetics and genomics medicine. How could you best describe what polygenic risk scores are?
Dr. David Duggan [00:01:55] Yeah, polygenic risk scores are another, more recent type of genetic risk assessment. So for decades now, we've known that disease has been passed down from generation to generation. We call that a family history. We also know that there are individuals who are born with a genetic change that might predispose them to Alzheimer's or breast cancer, but polygenic risk scores is something we discovered about 15, 20 years ago. And it's really just making its way into the healthcare system today. And what they are is a numerical value that actually summarizes an individual's genetic risk for predisposition to a particular trait, like high cholesterol or a disease, again, like cardiovascular or cancer disease. So it's really one number, that can summarize your risk for a disease A, B, C or D.
Karie Dozer [00:02:47] And is there a scale? I mean, is this a 1 to 10 number a 1 to 1 million number. How many numbers are possible.
Dr. David Duggan [00:02:53] Yeah. Good question. So there are a couple different ways apologetic risk score can be calculated. But perhaps the most common way is a is a solid number. Like you mentioned it's from zero to infinity. Although most numbers tend to be somewhere in the space of 0 to 10. And what that tells us if the number is greater than one, the individual has a one-point x fold or greater risk of actually developing disease than the population average. For example, men have a lifetime risk of about 12 to 14% of prostate cancer. We call that one x. But if you look at your genetics and the poly genetic risk score says you're at four times the risk of developing disease, your risk is actually significantly higher than that 12 to 14 x. It's more like 30%. So knowing your genetics can really retool your health care management going forward.
Karie Dozer [00:03:46] It's just one number and it represents your risk for one disease. So in theory, one individual could have hundreds of polygenic risk scores because they all applied to something different.
Dr. David Duggan [00:03:59] Yeah. That's correct. Although we've done the studies and there's been plenty of publications, fortunately many of these polygenic risk scores were discovered, validated and replicated using tens of thousands, hundreds of thousands, and even today, millions of individuals. So the scientific rigor behind these numbers is really solid. And what we're able to do when we have access to large population databases where there's half a million or more people, is we can ask the question you just asked so we can actually calculate hundreds to thousands of polygenic risk scores. But when you look at it, there's only about a dozen or more which are really clinically relevant. And of those clinically relevant polygenic risk scores, about a third of the population is at risk for one of those ten diseases. So not everybody is actually at risk based on their polygenic risk score. And less than a third is at risk for two or more. And then significantly less of the population is at risk for three or more.
Karie Dozer [00:04:58] It's just one factor, this number. If an individual has a particularly high number indicating a risk factor greater than typical for a particular disease, what are the other factors that actually affect that person's life and their probability of being diagnosed with that disease? Yeah.
Dr. David Duggan [00:05:16] So maybe a two-part answer here. First, before I get to your question, I want to emphasize that your genetics is not determination. Your genetics is this is a risk predictor apologetic risk score like most genetic tests predict risk. They don't diagnosis. There are exceptions Brca1 for breast cancer April maybe for Alzheimer's disease. But for the most part it's a risk prediction tool. It's not diagnostic. So in regard to your question about what other factors in addition to your genetics, might increase your risk, you're right. You're. Genetics alone, with exception, does not determine your disease susceptibility or whether you will develop this trait. The environment plays a key role in soda's lifestyle, and perhaps one of the more recent things that's driving my passion for getting this into the health care system is there's some very recent data in the last couple of years that shows even individuals who have a high genetic risk for cardiovascular disease, for example, a fourfold high risk. If they do modest changes to their diet and lifestyle, they can reduce their risk. 50%. That's amazing to me. I wouldn't have predicted that until we saw the data. So that's a clear example of how both genetics lifestyle in this particular case can be used to actually reduce your risk.
Karie Dozer [00:06:40] It seems ironic that something that shows a genetic risk in theory, could influence the way somebody lives. In other words, the genetic part of this information could influence all of those other factors which are anything but genetic. They're your choices.
Dr. David Duggan [00:06:56] Yeah. That's correct. And we'd actually in the future, and I hope I see this in the rest of my career. If not, if not afterwards, the more we can get this information into the health care system, into the public, into people, then they can use this actually minimally in their health care management. But there's actually also personal utility in not just polygenic risk scores but knowing your family history and your genetic susceptibility. So not only can this information be used to manage your health care, determine when you should start screening or whether or not you should go on this drug or that drug, or have this intervention. But you can also use it in your personal life, for example, financial planning. If you're at risk for late onset disease, you might want to start financial planning earlier. You may want to take that trip in your 40s or 50s if the disease is predicted to, you know, have an onset in your 60s. But again, let me emphasize that it's a risk prediction tool. It's not determination. So it allow you in addition to manage your health care, it'll allow you to perhaps make some changes in your personal life going forward.
Karie Dozer [00:08:02] You mentioned there's a small number, maybe ten diseases, that is currently used for what is specifically good for best for what are its best applications at this point in time.
Dr. David Duggan [00:08:14] So as I mentioned the polygenic risk scores, we can calculate polygenic risk scores as well. There are other genetic susceptibilities for hundreds and thousands of traits and diseases, a trait being cholesterol level, a disease being coronary artery disease or colorectal cancer, for example. But there's more factors that go into its accuracy and its performance. For example, polygenic risk scores perform best in traits or diseases that have what we call high heritability. So there's a large genetic component. They also work best in populations for which we've studied in great detail. And then also there are some other statistical and scientific factors that went into that. But to your question, for many of the common diseases coronary artery disease, breast cancer, prostate cancer, Alzheimer's disease, type two diabetes, these are some of the diseases where polygenic risk scores have high efficacy. So they have high utility in the clinic as well as personal life planning. There are some other diseases also I would say, cardiovascular disease, some other metabolic and obesity. So about 10 to 12, like I said. And they're mostly the common diseases that we're all either aware of or would prefer not to get as we get older.
Karie Dozer [00:09:32] Can someone's polygenic risk score change over, over time, over their lifespan?
Dr. David Duggan [00:09:36] So the polygenic risk score itself is something we're born with. Well, remember, it's a genetic changes, so we're not born with apologetic risk score. It's actually the genetic changes. We're born with those genetic changes, and we look at those genetic changes. So your genetics does not change over the course of your life. So in theory, we could measure your polygenic risk score at birth and predict diseases, you know, ten or 5 or 6 decades later in life, in practice, that probably won't happen until that individual's an adult. But I think there's arguments to be made that we can actually reduce risk for diabetes, for example, by changing behavior and lifestyle in children. So the polygenic risk score doesn't change. But what does change over time are the genetic variants. We might look at the algorithms and then the interpretation of these data. So while we only need to measure it once in an individual lifetime to predict, you know, those 10 to 12 diseases, we do want to touch base with our polygenic risk score as technology changes and as new information is brought forward.
Karie Dozer [00:10:41] You mentioned your passion is to get polygenic risk scores into health care, into everyday health care, something that we can all access. What does that look like? How big a job? Hub is that? And what, at the end of the day, what does success in that arena look like?
Dr. David Duggan [00:10:57] Yeah. So 20 years ago, Doctor Trent, Jones president, scientific Director talk to me about t gen and I was very excited to join him and Doctor Van Health and others here at t Gen. Not only do we focus on unmet clinical questions like we're talking about, how can we better predict who's at risk for disease, but they also make it available to us to translate those discoveries into the clinic or the health care. Translation is in the name of our institute, Translational Genomics. It begins with, sort of knowledge dissemination and, you know, working closely with health care administrators, doctors and others, other health care providers, a lot of education, you know, they they're busy taking care of patients. We're busy making discovery. So, we make it an effort through our collaborations and our institutional, relationships to get together with the health care providers, inform them of these new changes, raise awareness to them on how it can actually help their patients, and also help their practice at the same time, you know, efforts like these podcasts and other efforts at t Gen does, this information is getting out to the lay public. So hopefully by talking to the lay public as well as the health care professionals, not hopefully. I know we are making inroads into that goal.
Karie Dozer [00:12:21] How accessible is this technology to the everyday person? How able am I to get my polygenic risk score today?
Dr. David Duggan [00:12:29] Yeah, I would recommend, that the conversation starts with your health care provider, whether that's your primary care physician or genetic counselor, or a nurse practitioner. Talk to them about your family history. Talk to them if you're interested in learning more about your genetics. And they can put you in touch with the right people and the right people these days. And in some cases, it might be your primary care doctor, but in most cases, it'll be a genetic counselor where they can take a detailed family history. And then you can talk to somebody like a genetic counselor who has expertise in this area. And they can advise you appropriately on whether this test or that test is appropriate for your care. The nice thing about polygenic risk scores, as well as other genetic tests, what we've learned in the last ten years is genetic susceptibility to disease is not limited to families who have a history of disease. Polygenic risk scores is now applicable to 100% of the population. Whereas most risk, genetic risk has so far untold polygenic risk scores today were limited to those who have a family history. But we know disease affects people who also don't have family history. So talk to your doctor, talk to a genetic counselor or other health care provider to get that conversation started.
Karie Dozer [00:13:46] You've already sort of answered this question before I asked it, but once I have that information, once I have that score is everyone I meet in my health care journey going to know what to do with that information?
Dr. David Duggan [00:13:57] Unfortunately, the answer to that question is no. At the moment it is a new technology, genetics itself, and genomics is relatively new. Even though the human genome was sequence about 20 years ago, it's still an early technology. Genomic medicine is still in its infancy, but I would say whether your health care provider is aware of this information or not, start the conversation with that health care provider. And if you really do want to learn it and they don't have information for you there, there's resources available that National Genetic Counseling Society, for example. But I'm sure your doctor or your health care provider could put you in touch with somebody who can answer that question. Fortunately for us, the a number of individuals who are aware of what genomics can do for their patients and their and their practice is growing, and I think that will continue. And the speed is going to pick up as knowledge transfer, you know, picks up as well.
Karie Dozer [00:14:54] What about on the research side? Do people like yourself work on making these tests more reliable, more accurate as you go to work every day? What is on your to do list in this area? What needs to get better?
Dr. David Duggan [00:15:07] Yeah, the biggest challenge in this area is, the equity of the information. It's not equitable across all populations right now. Unfortunately, most of the discoveries and most of the research happened in individuals of northern European ancestry. Those are just the samples that happen to populate the databases. But there's been a concerted effort the last, you know, five years or even ten years to actually increase the representation from other populations African American, Asian, Latino, and so on and so forth. So, the big focus right now, as we know, polygenic risk scores have efficacy in all human beings. It's. Right now, their performance is better in some populations over others. So our efforts are focused on raising the level of efficacy so that it'll benefit all populations going forward.
Karie Dozer [00:16:03] What's involved in actually obtaining the information? Are we talking about a simple blood draw? What does that actual interaction look like?
Dr. David Duggan [00:16:10] If we're a patient or an individual who's interested in learning about their polygenic risk scores or any genetic risk, again, following the conversation with your health care provider. It's a standard workflow. So you would visit your, your physician or in this case, a phlebotomist or maybe even your doctor's office. It involves first, blood draw or a saliva sample, and then that blood draw or saliva sample is then sent to a genetic testing laboratory, a clear, certified laboratory. They isolate the DNA that's in that, in that material, and then they do some genetic testing. They might use a genotyping technology or a sequencing technology to learn about your genetics. And then your data is integrated into an algorithm. That algorithm has the information. And I mentioned on the genetic changes to look at which predict disease X, Y or z. And then your scores arrive like we're talking about your polygenic risk score for disease X, Y and Z will be determined. And then that information is provided to your physician where the interpretation part happen. So a little bit more than a blood draw I mean for the patient it's just a blood draw or a saliva sample. And the rest of that happens behind the scenes. So it's not terribly complicated and not invasive to the patient.
Karie Dozer [00:17:27] And it's also not personal in that you're not asking a patient or a person for information about family history. It's simply those physical characteristics that are measured, right?
Dr. David Duggan [00:17:37] Yeah, that I think is we're hoping could lower the barrier to entry. Family history, you know, can be spotty at best because not everybody knows whether grandmom had this or Grandpop had that, let alone and to your uncle. So family history is often incomplete. But the nice thing about personalized medicine or personalizing medicine is we just need you, your DNA, your genetic material that yes, you inherited from mom and dad, which inherited from Grandma and grandpa and so on and so forth. That's all we need to get this conversation started. Now, I don't want to leave the individual thinking family history isn't important. It is if you can get it, get it because it's a combination of family history, polygenic risk scores, you know, lifestyle and other clinical risk factors. That compendium is really strong and going forward with predicting your risk and assessing your risk. Any one alone is good. Start, but don't just stop with family history. Ask about polygenic risk scores. Ask about clinical risk factors and the like. So we like we like to have that whole compendium, going forward.
Karie Dozer [00:18:43] What have I missed? What have I not asked about this technology or the future and its use?
Dr. David Duggan [00:18:49] I would say probably three things. One, we didn't miss it, but I want to emphasize again that your genetics isn't determination. We're looking forward to bring this information. And we are bringing this information to the healthcare and to the consumer so that they can make both their physician and them personally more informed decisions about how to manage their health care or manage their lifestyle. So one, I just want to reiterate, genetics isn't determination. Two the technology is reliable and reproducible, in clinically useful applications. And there's a limited number of those applications. It's not going to solve all of our problems, but it's going to help us in some of those areas we talked about previously. Three, we need to keep pushing that technology with technological innovation, with, laboratory innovations. We hope to close that care gap. Like I said earlier in in the different population. So it's early in the in the research. Some of it is clinically useful today, but we're going to make more discoveries tomorrow and go through this cycle of, again, translating into the clinic. And again, it's a group effort that starts with the researchers and the clinicians, but ultimately serves the patients and the healthcare system. That's our ultimate goal.
Karie Dozer [00:20:07] Thanks for taking the time to explain. I'll let you get back to the lab so you can keep advancing your discoveries. Thanks so much.
Dr. David Duggan [00:20:13] You're very welcome. Thank you.
Karie Dozer [00:20:16] For more on TGen’s research, go to TGen dot org slash news. The Translational Genomics Research Institute, part of city of Hope, is an Arizona based nonprofit medical research institution dedicated to conducting groundbreaking research with life changing results. You can find more of these podcasts at TGen dot org slash TGen Talks, Apple and Spotify and most podcast platforms. For TGen Talks, I’m Karie Dozer.