Telomere Genetics Offer New Clues to IPF Risk: A Q&A With David Zhang, MD

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease for which there is no known origin; however, a recent study published in The Lancet Respiratory Medicine found that telomere length may contribute to disease risk in patients with IPF.¹

In this interview, the study’s lead author, David Zhang, MD, a pulmonary disease medicine specialist at Columbia University Irving Medical Center, dives into the study’s findings, revealing a promising breakthrough in IPF research and potential future therapies.

This transcript has been lightly edited for clarity.

The American Journal of Managed Care^® (AJMC^®): What motivated you to combine rare damaging variants and polygenic risk scores (PRS) to define genetic endotypes in IPF?

Zhang: Great question. I think for a long time, the genetic risk of IPF has either been examined from a common variant standpoint through genome-wide association studies or from a rare variant standpoint through exome sequencing. I also think the time has come now, with new technologies, where we can assess all of these genetic risk factors at the same time. Limitation, previously, was more of a technological one; it's a different analysis and different technology to look at common variants vs rare variants.

But now, through whole genome sequencing, we can get at all of those risk factors at the same time. There's been a lot published, almost in parallel, about rare and common variants for IPF, but not as many, or really, not many [studies] at all that try to integrate both of those at the same time. We think [with] IPF, there's still a lot of genetic risk that's missing. We're really just looking at 2 independent sides of the story without putting them together. This is what we're trying to do with this paper.

AJMC: The MUC5B promoter variant was associated with IPF across all endotypes. Why do you think it remains such a universal risk factor, even among rare variant carriers?

Zhang: The MUC5B variant is one of these curiosities in genetic medicine, where it's such a strong risk factor, yet it's so common across the population. In other examples in genetics, when there are common variants that have that kind of behavior, usually there are dual effects, where it's protective for one thing but a risk factor for something else.

The common example I give to people is about risk of chronic kidney disease in African Americans, where that is a protective risk factor for certain types of infections but an increased risk factor for chronic kidney disease; sickle cell disease is another one of these examples. I think we don't know exactly, but there have been studies showing that MUC5B is protective against severe COVID, and so there's this sort of link between maybe protection against respiratory infections, but an increased risk for IPF.

To get to the question of why it's such a universal risk factor, I don't think that we still know, but it is clear that even among the rare variant carriers, this finding would suggest that there's something extra needed on top to push somebody over the edge to developing disease. I think that's part of one of the most exciting parts of the study as well.

AJMC: By contrast, the PRS excluding MUC5B predicted risk in noncarriers but not in rare variant carriers. What does this reveal about genetic heterogeneity and risk modifiers in IPF?

Zhang: I think this is also one of these findings where it really speaks to how complicated all these different risk factors are, and it's not like they're just additive for everybody with IPF. The fact that this particular polygenic score was not associated with rare variant carriers implies that at least this set of common risk factors is not necessary for individuals who have rare variants to then have this set of additional risks.

About the polygenic score, that is another question that we don't have all the answers for. But I think this just shows that not everybody has the same amount of genetic risk factors pieced together to develop a disease. Some people have one set combination of genetic risk factors, and others have a different sort of combination, and I think these findings show us that.

AJMC: Telomere length PRS was linked to IPF risk in both carriers and noncarriers, with the strongest effects in patients with very short telomeres. How might telomere biology represent a shared pathway across distinct IPF subgroups?

Zhang: I think the most powerful part of studying the telomere length genetics is that it really points to a causal molecular phenotype, as we've described it. When we think about what is causing IPF, all these different risk scores might really be a combination of different disease pathways that are being represented. The telomere polygenic score and the rare variants, which happen to be mostly telomere-related, are a bit more focused toward a single disease pathway. I think what this study is showing is that for the individuals who don't have a rare mutation but still have a very short telomere length, it's really the telomere polygenic score that is leading to shortened telomere length that is then somehow leading to IPF. Even though you know the polygenic score and the rare variants are different genetic risk factors, they converge on short telomere length, and that leads to IPF.

The reason why that is still relevant and interesting, I think, is because of the genes that are represented, or even going 1 step back, what are the pathways leading to a short telomere length that can even come from diverse pathways? Ultimately, this is telling us that, yes, telomere length is this proximal step for IPF, but how we get to short telomere length from a genetic standpoint is quite diverse and very relevant for IPF, and especially for those who have these unexplained short telomere lengths.

AJMC: How could these genetic endotypes eventually help clinicians stratify patients, for example, by identifying those at higher risk for rapid progression or treatment-related complications?

Zhang: It's known already that telomere length has these associations with poor outcomes and rapid progression. I think one way I think about this is that telomere length itself can come from a variety of different sources. Somebody who has chronic inflammation or chronic infection, even without having that genetic risk factor, can have short telomere lengths. This analysis gets back to what is causing it to begin with.

Another factor is that telomere length might change over the course of somebody's lifetime, whereas these genetic risk scores are the same throughout somebody's entire life. There might be a little bit of precision in terms of finding individuals who have the outcomes. We haven't done those studies specifically, but that's something that would be interesting to look at. But also, I think this tells us a little bit more about what we're looking at when we measure telomere lengths and individuals. Now we know that this is still representing something that's inherited rather than something that's acquired, at least as it pertains to IPF.

AJMC: How might these genetic tools help improve screening and risk prediction for families affected by pulmonary fibrosis?

Zhang: One thing that we're excited to take as a next sort of part of this story is how we can use this now to explain or predict risk in higher-risk individuals. Specifically, how that pertains to individuals who have a family history of pulmonary fibrosis. I am using this to not only improve diagnosis but also incorporate it into screening practices, and I think it is going to be a very promising tool as well.

We're excited to see where that might take us, and familial pulmonary fibrosis and those who are relatives of patients who have IPF, we think, are the prime populations who would benefit from making these tests more precise. We’re also excited to see where that goes, and I think there are a lot more opportunities, but I think this is just the beginning.

References:

McCrear S. Telomere length and polygenic risk shape endotypes in idiopathic pulmonary fibrosis. AJMC. AJMC. February 3, 2026. Accessed February 13, 2026. https://www.ajmc.com/view/telomere-length-and-polygenic-risk-shape-endotypes-in-idiopathic-pulmonary-fibrosis