Researcher studies genetic factors tied to a lung disease

Host Amber Smith: Upstate Medical University in Syracuse, New York, invites you to be The Informed Patient, with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith.

A lung disease that affects more than 11 million Americans is called COPD, for chronic obstructive pulmonary disease.

Host Amber Smith: A researcher from Upstate wonders whether there are genetic factors that contribute to the disease or that protect people from developing COPD.

Dr. Auyon Ghosh, an assistant professor of medicine at Upstate, recently was awarded a $1 million grant from the National Institutes of Health to investigate, and he's here to tell us about his work. Welcome to "The Informed Patient," Dr. Ghosh.

Auyon Ghosh, MD: Thank you for having me.

Host Amber Smith: I'd like to start by asking you to tell us what we know about COPD.

Is this a disease that smokers get?

Auyon Ghosh, MD: Yeah, that's exactly right. Smokers are at higher risk of COPD than the general population, but there are a lot of other things that can affect a person's risk for COPD.

Host Amber Smith: What are some of those other things?

Auyon Ghosh, MD: In the U.S., the predominant risk factor is cigarette smoking.

But in developing countries and low- and middle-income countries, a growing number of people are at risk for COPD based on their exposure to air pollution.

Host Amber Smith: In America then, what percent of COPD cases are because of smoking? Is that the majority of them?

Auyon Ghosh, MD: It depends on how you look at it.

About 40% of smokers develop COPD, but of folks who have COPD, about 70% of those folks are smokers.

Host Amber Smith: So what are the symptoms?

Auyon Ghosh, MD: The symptoms of COPD kind of have this classic triad, as we call it: three cardinal symptoms of COPD. First is a cough that doesn't go away; excess sputum production -- making, coughing up a lot of phlegm; and then feeling short of breath.

Host Amber Smith: So how does a person typically discover or get diagnosed with COPD?

Auyon Ghosh, MD: The usual way that this happens is that a person will have these types of symptoms, whether it's the cough, or the shortness of breath at rest, or when they're exerting themselves, and that'll bring them to see a doctor.

Once they see a doctor, usually they'll get referred to a pulmonologist, someone like myself, who will perform what are called pulmonary function tests, and that's kind of what we use to diagnose COPD.

Host Amber Smith: Are most of the people with COPD older people?

Auyon Ghosh, MD: Generally speaking, yes. The average age of diagnosis is in the early 60s, but in certain individuals, it can be a little bit earlier.

Host Amber Smith: And does it affect men and women the same?

Auyon Ghosh, MD: So part of the disparity or the difference in, the number of men and women that were affected by COPD, came down to differences in the rates of smoking that have changed over time. Fifty, 60 years ago, it was predominantly a disease in men, but as smoking rates increased in women, the number of women with COPD also increased.

Host Amber Smith: Now, does a person who is diagnosed with COPD, does it keep getting worse as they age?

Auyon Ghosh, MD: So for some, lung function can get worse as they age. For others, the lung function can kind of get bad and then stay at the same level. So the trajectory, or the rate at which lung function changes, can vary from person to person.

Host Amber Smith: Now, you mentioned the pulmonary function test to help diagnose. Do you use that to track where they are and if it's gotten better or worse, too?

Auyon Ghosh, MD: Yeah, certainly. At different periods of time for different folks, we'll repeat those pulmonary function tests to see what a person's lung function is doing over time.

Host Amber Smith: Are there effective treatments?

Auyon Ghosh, MD: There are great treatments that are out there to help with symptoms, but there really isn't a medication or some other treatment that can reverse the damage to the lungs or sometimes even slow the lung function decline. The best treatment that's out there is quitting smoking.

Host Amber Smith: Well, I'm anxious to hear about the project that received the grant. Now, this is from the NIH's National Heart, Lung and Blood Institute. What will you be looking at?

Auyon Ghosh, MD: The idea here is, and what we touched on a little bit earlier, is that really only a minority of smokers, about 40% of smokers, get COPD. So a significant portion of folks who are at risk, people who have smoked, don't develop COPD. And the question here is, what makes those folks different? We have done a lot of work in trying to better understand who's at risk, but we don't have a great understanding about the folks who are resistant, or as we call it, resilient, to developing COPD.

Host Amber Smith: Do you have ideas about why only 40% of smokers get COPD?

Auyon Ghosh, MD: We do, and some of the results that we've already seen are what we're going to be exploring further in this grant. Specifically, we know that there are certain genetic variants, or specific genes, that a person can have that puts them at higher risk.

What we want to know is, are there other genes, or other genetic variants, out there that reduce that high risk? So for folks who are at high risk because they smoke, or if they are at high risk because of the specific genes that they have, are there other genes that can mitigate those effects? Are there other genes that can kind of tamp down on the genes that cause a higher risk?

Host Amber Smith: So there might be a genetic reason that 60% of smokers seem to be protected from developing COPD. Is that what you're saying?

Auyon Ghosh, MD: Yeah, that's exactly right. and we are going to try to look for the genes, or the groups of genes, that can be protective.

Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith.

I'm talking with Upstate pulmonologist and assistant professor of medicine Dr. Auyon Ghosh. We're talking about COPD and a research project that Dr. Ghosh recently received grant funding to conduct.

Well, I understand you'll be working with studies that involve more than 60,000 people. They're not all from Syracuse, right?

Auyon Ghosh, MD: No, no, no. The individuals who are a part of this study belong to studies that already exist. The NIH over many decades has developed and funded many different studies across the country that have recruited folks from different geographic areas, folks who belong to different demographic groups, and, over time, have collected the DNA samples and other molecular samples that are now available to the research community.

And so the idea here is that we're going to be able to use these 60,000 samples that have been collected over a long period of time to get additional insights from these samples that have already been collected.

Host Amber Smith: So some of them will be from people who have COPD, and some of them will be from people who don't? Is there a mix like that, or are you looking just at people with COPD?

Auyon Ghosh, MD: For the purposes of this project, we actually need, specifically, folks who don't have COPD, and we need to understand the folks who either have smoked or have high genetic risk of COPD but don't actually develop COPD.

What makes those folks different?

Host Amber Smith: I see. So how will your work be done?

Auyon Ghosh, MD: The project comes down to three different arms, or, as we call them, aims.

The first aim, we're trying to identify a set of genes that are protective, that contribute to what we're calling genetic resilience. So the idea here is that we're going to, first, identify the folks who are at high risk by looking at what's called a polygenic risk score, and I'll take a minute to talk about the polygenic risk score now. The idea is that each individual gene there has a variable amount of effect on a person's risk of developing COPD, for instance, but over the entire genome, which is millions and millions of these genetic variants, about seven and a half million, to be exact, about 2.5 million of these genes contribute to the genetic risk. And these contributions are very small, but when you add it up, over 2.5 million genes, that's when you can kind of figure out, OK, it's this person because their, 2.5 million genetic variants are at X amount of risk. And the next person, because of their 2.55 million genetic variants, are at Y amount of risk. And the idea here is that there are 5 million other genetic variants; how do these affect that risk?

Our goal is to take the folks who have the high polygenic risk score, meaning we've summed up the effects over those 2.5 million genes, and then we're going to look for differences in the other 5 million genetic variants to see how those 5 million variants affect that higher risk.

And so the polygenic risk score, again, basically puts together the information from millions and millions of variants, and then the polygenic resilience score, similarly, will be putting together the effects of another large set to see how those two things work together.

So going back to your question, the first part of what we're going to try to do is identify these genetic variants that reduce, or can help mitigate the effects of, folks who are at high risk.

The second part is to identify what are some other factors, like nongenetic factors, whether it's demographics or medical history or things like that, that can contribute to what we're calling resilience.

And then the third is to see how we can find molecular signals in the lung that are related to this resilience idea.

Host Amber Smith: So this polygenic risk or resilience score that you mentioned, has this been used in research previously?

Auyon Ghosh, MD: One of my collaborators actually developed the first polygenic resilience score for COPD, and that's what we're going to be using to identify these folks who are at high genetic risk.

And the concept of polygenic risk scores has been developed in a bunch of other diseases, namely, heart disease and heart attacks, diabetes and so forth, to identify folks who are at high genetic risk for these things to happen. Now, this type of research is still in the early stages; it hasn't been really been deployed outside of the research context. But the hope is that by identifying folks who are at high genetic risk, that we can find ways to intervene before the disease really gets going.

Host Amber Smith: That's a little ways off though, right?

Auyon Ghosh, MD: Many, many, many years off, but that's the hope.

Host Amber Smith: But if your project does show that there's a gene or a collection of genes involved in either the risk or the resilience, then you can build on that and hopefully come up with some information that would help people.

Auyon Ghosh, MD: Absolutely. That's the goal.

Host Amber Smith: Well, Dr. Ghosh, thank you for making time to tell us about your work. I appreciate it.

Auyon Ghosh, MD: Thanks. It was a pleasure.

Host Amber Smith: My guest has been Upstate pulmonologist and assistant professor of medicine Dr. Auyon Ghosh.

"The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe.

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