Moderate to Severe Asthma Podcast

Asthma Is a Genetic Disease. Why Does That Matter?

Michael Wechsler, MD; Benjamin Raby, MD, MPH

Disclosures

August 16, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Michael Wechsler, MD: Hello. I'm Dr Mike Wechsler. Welcome to Medscape's InDiscussion series on moderate to severe asthma. Today we'll be discussing asthma genetics and asthma pharmacogenomics with Dr Benjamin Raby. Benji is the chief of the Division of Pulmonary Medicine at Boston Children's Hospital, and he's the Leila and Irving Perlmutter Professor of Pediatrics at Harvard Medical School, and he also serves as the director of the Brigham and Women's Hospital Pulmonary Genetics Center.

He has a clinical operation and a research operation, and he also serves leading the youngest, brightest minds in pulmonary pediatric medicine. It's great to have Benji. Welcome to InDiscussion, Benji. Tell us a little bit about yourself.

Benjamin Raby, MD, MPH: It's really a pleasure to be here. I am a pulmonologist trained at McGill University in Montreal, Canada, my hometown. I moved down to Boston about 20 years ago and have been studying the genetics of lung disease, particularly asthma, for the past 20 years. I'm a practicing clinician, as you pointed out. I see patients at our Pulmonary Genetics Center, where we're referred patients with suspected forms of genetic lung disease. We provide diagnostic services and evaluation management plans. At Boston Children's Hospital, I have a wonderful team of faculty who take care of children with a variety of lung diseases — particularly many with asthma, severe asthma, in fact.

Wechsler: Great. How did you first get into studying genetics of lung disease and genetics of asthma, specifically?

Raby: It's a funny story, actually. I had finished my pulmonary training and was thinking about what I was going to do next. I wanted to take a shot at doing a little bit of research and got some advice from my father-in-law, who was actually the chair of genetics at McGill University. He told me about a guy who was just coming from having finished working at the Whitehead/MIT Center for Genome Research on the Human Genome Project, who was now studying the genetics of asthma and other lung disease. He thought that that person, Dr Tom Hudson, would be a great person for me to work with. I went over there, I didn't know the first thing of what I was doing, but within a few months, he had gotten me up and running, and the rest is history. To quote one of my other mentors, he said, "Oh! Really nice. Good Jewish boy going into the father-in-law's business." So, we're now both doing genetics and loving it.

Wechsler: Great. So, 25 years later, do you know the first thing about asthma genetics now, or are we still learning?

Raby: We're still learning, but we've come a pretty long way.

Wechsler: I've been working clinically with asthma patients for a number of years. One of the things that I've recognized is that there are a lot of patients with asthma who have siblings with asthma, parents with asthma, and/or kids with asthma.

How often does asthma run in families?

Raby: It's pretty frequent. The vast majority of patients with asthma, if you dig deep enough, will have a family history. The most proximal is usually the parent. Very often there's a maternal history of asthma. Mother's history of asthma is much more of a risk factor than father's history of asthma. We're not exactly sure why that is. Among siblings, the older siblings are often the ones who manifest asthma more frequently than the others, but in families, you end up seeing sometimes two or three children who have similar presentation. Overall, we think that asthma is about 50%-60% genetic, meaning that there are both genetic and environmental determinants and risk factors. From a number of twin studies and other population genetic epidemiologic studies, it seems that about a good 50%-60% of the overall risk can be explained by genetic factors.

Wechsler: So, over 50% is explained by genetics and the rest is environmental?

Raby: It depends how the studies are done, but it turns out the more precise your definition of the diagnosis — so if a diagnosis includes, for example, objective measures of airways responsiveness, methacholine challenge testing, if you have an established MD diagnosis and a history of multiple anti-asthma medications — that increases the precision of these estimates. And in those studies, the estimates are as high as 70%.

Wechsler: There's a real genetic basis here. How does this degree of heritability compare to some of the other traditional genetic disorders like cystic fibrosis or sickle cell disease?

Raby: This is where things get more complicated. Those diseases that you mentioned are what are referred to as monogenic or Mendelian single-gene disorders. They are caused, like cystic fibrosis, by mutations that have a major genetic impact on the function of a gene. All you need is to have those mutations in that one gene, and you'll get the disease. So, the relationship between having the risk gene and having the disease is almost 100%. Asthma is very different. There is no one gene that causes asthma, and if you had that alone, you would develop asthma. Instead, it's caused by a number of genes, each with much weaker effect. Because those variants aren't having a massive impact on the proteins, but rather subtle effects, you need to have multiple of these genes working together. If we have a patient who has the mutations that cause cystic fibrosis, we can say a lot about whether or not they're going to develop cystic fibrosis. The same cannot be said when we find a given gene that we know can cause asthma. The person may or may not develop asthma even if they have the risk variants.

Wechsler: If someone has a genetic predisposition to asthma, but they don't have the environmental exposures that often lead to asthma — like exposure to dust or pollen or cats or dogs or any of the other things that are commonly associated with asthma — will those patients just never manifest asthma and never become diagnosed with asthma?

Raby: Some of them won't. But if you have enough of a genetic load, then you will likely still manifest the disease, at least some features of it, even without having a significant environmental exposure.

Wechsler: I've seen a lot of people recently who haven't had any history of asthma, but they've been coughing and wheezing in response to all the wildfires that come from our home country up in Canada. Do you think that many of those people have a genetic predisposition, but they never had this sufficient environmental exposure?

Raby: I think that that's probably true in many cases. Of course, there are things like reactive airway disease and other types of airway diseases that can be caused by pollutants. For many patients, it's the environmental exposure that's necessary to unmask this genetic predisposition that they've been carrying around their whole life. We know in many different clinical settings, not only in lung disease but also in genetics in general, that if you don't have the right environment, the prevalence of disease will be much, much lower.

Wechsler: That's a really important consideration. When I see my patients, I try to take a good history and obviously do a physical exam, including their lung function. I think the history of both environmental factors and the family factors are really, really important to get at when trying to ascertain whether or not a patient has asthma or something else.

What are some of the other conditions that are associated with asthma that also have a genetic predisposition? What about nasal polyps? What about chronic sinusitis? What about atopic dermatitis? Do those all travel in families together in the same kind of patients, the same genetic predispositions?

Raby: There are a few things that you brought up there, but starting with the last point, we know that, for example, atopic dermatitis has a very strong heritability. At least 45%-50% of that is also thought to be genetically determined. If you look at the studies that have actually mapped the genes that cause atopic dermatitis, we know a lot of them overlap with genes that also cause asthma. Very often, those things will run together. With that triad of atopic dermatitis, allergic rhinitis, and asthma, there's a lot of sharing of genes. There are some genes that are very specific to each one of those conditions, but many of them overlap.

Another huge area of overlap, or at least modification interaction, is with obesity. We know that obesity is a genetically determined condition, in part. Obviously, caloric intake and exercise are two other major factors, but there are many shared genetic determinants between obesity and asthma. We know that each modifies the expression of the other.

Lastly, I think it's important to mention from earlier on in our conversation that not only does the environment play a really important role in the expression of the disease, in whether someone will develop asthma or not, but where it plays an even bigger role than genetics is in the control of the asthma and the severity of a person's asthma.

When we formally test the heritability of severe asthma, are all the kids having severe asthma or is only one or another? It turns out that the heritability is much, much lower for asthma severity, only about 25%. That's where the environment really plays a role. You must reduce those environmental exposures to improve control and decrease exacerbation.

Wechsler: We can work on mitigating someone's environmental exposure. We can give people treatments. Why is it so important that we understand the genetics component? What has come of what we know of genetics of asthma into the clinical realm?

Raby: I think that there are three or four important motivations of why we've been looking to find these genes. In the early days, when we didn't really have a great understanding of what we were going to find and what the true genetic composition would be, we thought we were looking for just a few genes. And if we found those genes, we would be able to, through a combination of a few factors, predict and diagnose and be able to tailor therapies. There was a lot of hype about that promise. A lot of that hasn't panned out as we would like, because of what I mentioned earlier about how no one genetic factor is predictive — we need many of them. What we're starting to see is that by developing prognostic scores based on many of these variants, we can actually start identifying those people who are at the highest and lowest risk of developing disease. Among those with the highest, we can see a future not too far down the road where we can think about early intervention in children who are in that highest percentage of risk in terms of going into the house and trying to mitigate some of the environmental causes.

Wechsler: That's really important. So, the thinking is that if you can identify people who've got a significant genetic risk, and you treat those patients early on, you might have a significant impact. The goal would then be to identify those people and recognize that they are at risk. We can keep an eye on them and/or treat them, and prevent the asthma from occurring. You're really talking about modifying the course of the disease in those individuals.

Raby: And also the establishment of it. If we can get to some children early enough — and we don't know if this will be the case — we hope that we'd be able to intervene. There have been some home intervention studies in broad swaths of the asthma population where we just estimate risk based on whether or not there's a family history. Here, we're talking about not taking all of those patients but really those at the highest risk and trying to intervene there. Those studies will probably start being able to be done because we now have enough genetic information to classify people. Hopefully we'll have some answers to those questions in the not-too-distant future.

Wechsler: Tell me what advances we have in terms of identifying specific genes. How many genes have we identified that really correlate well with asthma diagnosis and/or treatment? What are the top hits, so to speak?

Raby: To summarize it briefly, we now have about 80-90 genes and variations in those genes that individually contribute risk. How much risk? Well, some only increase risk by 5% or 10%, some even lower. Through that combination, we can now explain about 30%-35% of overall genetic risk.

Of the top genes, some of the ones that keep coming up over and over again in these studies and have the highest effect estimates are genes like IL-13, TSLP, and some of the other cytokines and their receptors, like IL-33, an alarmin, IL-4, the IL-6 and IL-6 receptors.

But then there's some new genes that have been identified that we never would have suspected before based on what we knew. The top hit there is really this chromosome 17q region that includes a few genes that we think work together, including ORMDL3 and gasdermin B (GSDMB). Researchers, including our group and many others, are still trying to figure out exactly what those genes do. But we're hopeful that that's going to open up some new avenues for developing therapeutics.

Wechsler: We know that there's all sorts of different phenotypes of asthma, allergic asthma, eosinophilic asthma, and type-2 and non-type-2 asthma. We also know that there's adult-onset and childhood-onset asthma. Has there been any insight gained from some of the genetic work you've been doing that has tied into the phenotype-genotype interactions?

Raby: Those studies are exactly where we want to go with this. We do envision that it would be fantastic if we could take a collection of genes and say, "This person has a signature that says they have this type of asthma, and we should be treating them in this particular way." Unfortunately, we're really not there yet. The only thing that we can say for sure is that many of the genes that we've identified are really important in predicting childhood-onset disease and are very different from some of the genes that are in adult onset. There are very few examples, if any, that would give us a specific phenotype. The one exception to this is a gene called filaggrin, which can cause a rare disease called ichthyosis vulgaris, which is a dermatologic condition. If you have copies of those variations, your risk of very severe asthma is markedly increased, and those people all present with atopic dermatitis.

Wechsler: Wow. That's fascinating, and it's so important to try to keep on teasing out some of these genomic differences. Has this led to any pharmacogenomics, and can you talk a bit about what pharmacogenomics is for our listeners? How do you see genetics playing a role in terms of giving the right drug to the right patient at the right time? How can we move the needle forward from using biomarkers to using genomics for precision medicine?

Raby: Wonderful. So, first thing to say is that the same way we do studies to identify the genes that cause asthma, there have also been many studies that then look at the genes that predict response to therapies. Those studies have been done for response to beta adrenergic therapies. They've been done for inhaled corticosteroids, leukotriene-modifying agents. Those pharmacogenetic studies are looking for variants that predict response. There have been some studies that have clearly identified genes that do predict response. Unfortunately, those effects, like what we see for asthma, are weak and are not individually strong predictors.

We still don't have any genetic test that we can use to say, "You should be taking this medication and not that medication." The other problem that we have right now with those studies is that very often, we don't have an alternative. If the study shows that this patient will not respond to this therapy, what are we going to put them on instead?

I think as we start doing more of these studies with biologics where we know a variation, particularly a rare variation, in the targets of those biologic medications, we may alter the response to therapy. For those therapies, they're not cheap. It would be great to be able to know in advance that we really shouldn't be trying this medication in that patient and really going to an alternative that targets a different protein.

Wechsler: Isn't it hard to do those kinds of pharmacogenomic studies? The general studies in asthma — the phase 2 studies, phase 3 studies — there's somewhere between 500 and 1500 patients. Is that enough to help us identify pharmacogenomic targets that will better predict response? Or, do we need to do much larger studies that look at larger populations?

Raby: You're right on the mark. If we think about genetic studies in general, we're talking about doing them in thousands of people. The problem with pharmacogenetic studies is they typically have to be done in the context of a clinical trial. The clinical trials are rarely of a sufficient size to study the genetics because those studies are specifically powered to detect the treatment effect irrespective of genetics. What we really need to be able to do is to pool studies across different trials and put all of those data together to map these genes. Unfortunately, that requires a lot of collaboration and cooperation among pharma, academia, and government, and that's been very challenging to do.

Wechsler: Yeah, not to mention that there are a lot of patients around the world — not just in the US but across Europe and Asia — that will make it even more challenging to get sufficient numbers because it's hard to do those kinds of international collaborations. What are your thoughts about the future directions of asthma genetics and pharmacogenomics? What should we expect 10 years and 15 years from now?

Raby: The immediate future will depend on doing three things. One is trying to figure out what the genes that we've already identified actually do, and which of those can be truly modified through pharmacology to better treat asthma. That's a major priority. We've identified 100 genes, and we've got to figure out what they all do. We already know what many of them do. There have been drugs that are already targeting those genes. For example, there are drugs targeting TSLP, IL-33, and IL-4 and their receptors.

We must keep moving down that road. Secondly, what I mentioned before about these cumulative predictive risk scores, that is a major area of endeavor right now. Over the next few years, I foresee understanding how better to use those to be a huge player in trying to prevent the establishment of disease in those children at highest risk. And further down the road, the hope is that we will have an armamentarium of medications, and that we will be able to tailor them somewhat based on their overall genetic signature. That's still a ways away, but we do anticipate that we're going to get closer to that as we get more precise therapies and a much more precise idea of the genetics. If I can end on one point, I think of all the things that we've learned so far, the one that I think is most important for clinicians to know is that these studies have been done in patients from all over the world of all ethnicities, and the top hits that we've identified are the same genes in every ethnic group.

So, although there may be rare variants that explain some of the differences in both the prevalence of disease and the natural history of disease across racial groups, overwhelmingly, the disparities that we see in asthma across ethnic groups is not likely to be related to genetics and much more related to the environmental exposure, access, cultural, and social issues that we need to address.

Wechsler: Amazing. Great. We've learned so much today. I think the key takeaways are asthma is a genetic disease. We're learning a lot about the genetics of asthma. In the future, we're going to try to identify other genetic loci that will help us apply more precision medicine principles to our patients and give the right drug to the right patient at the right time based on genomic signatures.

This has been a terrific discussion. We've had national expert Dr Benjamin Raby discussing asthma genetics and pharmacogenomics. I want to thank our listeners and Benji. Thank you all for joining us, and we look forward to our next session of InDiscussion. Again, this is Dr Mike Wechsler.

See you next time.

Listen to additional seasons of this podcast.

Resources

Asthma

Pharmacogenetic Factors Affecting Asthma Treatment Response. Potential Implications for Drug Therapy

The Human Genome Project

Methacholine Challenge Test

Obesity and Asthma

The Cytokines of Asthma

Bronchial Allergen Challenge of Patients With Atopic Asthma Triggers an Alarmin (IL-33, TSLP, and IL-25) Response in the Airways Epithelium and Submucosa

ORMDL3 and Allergic Asthma: From Physiology to Pathology

New Insights Relating Gasdermin B to the Onset of Childhood Asthma

Hereditary and Acquired Ichthyosis Vulgaris

The Role of Filaggrin in Atopic Dermatitis and Allergic Disease

Precision Medicine in Childhood Asthma

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