Genetic risk tied to IBD severity

Patients with a higher genetic risk for inflammatory bowel disease were significantly more likely to experience a severe disease course, including major surgery, repeated hospitalizations and greater medication use, according to a nationwide Danish cohort study published in Gastroenterology.

The study analyzed polygenic risk scores, or PGS, for IBD susceptibility in 8,267 patients from Danish registries through September 2022 (3,732 with Crohn’s disease and 4,535 with ulcerative colitis) and found a dose-response relationship between genetic risk and disease severity over time. Compared with patients in the lowest PGS quintile, those in the highest quintile had more than double the risk of major IBD-related surgery in both Crohn’s disease and ulcerative colitis.

“We need tools to enable personalized medicine within IBD to improve patient outcomes,” the study’s corresponding author Marie Vibeke Vestergaard, PhD, of the Center for Molecular Prediction of Inflammatory Bowel Disease in the Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark, told GI & Hepatology News. “Without this stratified approach, some patients experience prolonged uncontrolled inflammation and progressive damage while waiting for the optimal treatment for them, while others might be overtreated with expensive medicine with considerable side effects. Our hope is that this study can contribute with new insights on how to better stratify patients in the future so that more patients will receive the right treatment from the start.”

Using Cox proportional hazards models adjusted for sex, age at diagnosis, calendar year, cohort and genetic ancestry, the investigators reported a hazard ratio of 2.74 for major surgery in Crohn’s disease and 2.04 in ulcerative colitis when comparing the highest with the lowest PGS quintile. Time to prolonged IBD-related hospitalization (defined as more than two days) was also shorter with increasing genetic risk (HR 1.81 in Crohn’s disease and 1.69 in ulcerative colitis).

Beyond discrete events, higher PGS was associated with biochemical markers of more active disease. At diagnosis, each standard-deviation increase in PGS corresponded to higher fecal calprotectin levels in both Crohn’s disease (β = 0.27 log mg/kg) and ulcerative colitis (β = 0.21 log mg/kg), as well as lower hemoglobin levels in both conditions. Elevated C-reactive protein was observed with higher PGS in Crohn’s disease but not in ulcerative colitis.

To capture overall disease burden, the researchers defined a composite severity outcome based on events within three years of diagnosis, including hospitalizations, surgeries and cumulative systemic corticosteroid exposure. Severe disease occurred in 31.6% of patients with Crohn’s disease and 27.3% of those with ulcerative colitis. Each standard-deviation increase in PGS was associated with higher odds of severe disease in both groups (OR 1.25 for Crohn’s disease and 1.33 for ulcerative colitis). In absolute terms, 39.2% of Crohn’s disease patients in the highest PGS quintile developed severe disease, compared with 23.6% in the lowest quintile.

Intensity of treatment tracked closely with genetic risk. Among patients diagnosed since 2003, higher PGS was linked to increased use of biologic therapies, immunomodulators and systemic corticosteroids within three years of diagnosis. For example, the odds of receiving biologic therapy rose by 35% per standard-deviation increase in PGS in Crohn’s disease and by 31% in ulcerative colitis.

Subgroup and sensitivity analyses revealed differences between the two diseases. In Crohn’s disease, much of the association between PGS and disease severity was attenuated after adjusting for disease location (ileal, colonic, or ileocolonic involvement), suggesting that where the disease is located helps explain this relationship. In ulcerative colitis, the results changed very little after adjusting for disease extent, indicating that the same genetic factors influence both disease risk and severity regardless of how much of the colon is affected.

Dr. Vestergaard described the positive association observed between the combined genetic risk of getting IBD and the severity of the subsequent disease course as “surprising and provides new insights to the etiology of disease severity linking increased susceptibility to increased severity,” she said. “But what was most surprising was that the association appeared to be mediated by the location of the disease in CD. Thus, genetics influence where in the gastrointestinal tract you will get inflammation and then the location influences the disease severity. This was, on the other hand, not found to be the case for UC.”

The authors noted several limitations of the study, including restriction to patients of European ancestry, incomplete laboratory data for some participants and potential selection bias in analyses relying on pathology records.

“Genetics cannot stand alone in this clinical prediction tool,” Dr. Vestergaard added. “We need other biomarkers on disease severity, treatment response and so forth to be able to reach the goal of personalized medicine within the field of IBD.”

The study received funding from the Danish National Research Foundation, the Lundbeck Foundation, the Novo Nordisk Foundation, and the Colitis-Crohn Foreningen. Dr. Vestergaard had no disclosures to report.

GI & Hepatology News invited Greg Gibson, PhD, professor of biology and director of the Center for Integrative Genomics at Georgia Tech, to comment on the study.

Why is this study important?

Dr. Gibson: First, it overturns the accepted almost a decade-old opinion that polygenic scores (PGS) for IBD susceptibility do not associate with disease course or severity.  This study shows clearly that they do in the Danish setting.  Second, it refocuses our attention on prediction of disease course, which has much more potential utility than attempting to predict disease onset.  

What are the potential clinical implications of the research?

Dr. Gibson: I think it is underappreciated that precision (positive predictive value) of IBD is never going to be useful for a rare disease like IBD just because the case-control ratio is so small in the population. By contrast, if 30% of the patients advance to severe disease, as is the case in these two typical studies, then PPV can be 75% for a good predictor. We’re certainly not there yet, the authors acknowledge that, but they have a line in the discussion that I think is great: “We are approaching a stage in the clinical handling of patients with IBD, where we need to discuss when it is time to introduce the PGS – potentially in combination with other molecular factors – to inform patients of their odds of progression, hence guiding joined decision making on treatment choices.”

I am not a clinician, so I do not have a good sense of what patient needs are, but I should think that they would like to know (1) their prognosis and (2) which treatment course is most appropriate for them. At some point in the future, I should think that PGS will be part of that determination, and really for the first time, we have reason to hope that there is utility of using genetic risk as part of the information that patients and physicians use to make decisions.

What additional research may be needed/what questions remain unanswered?

Dr. Gibson: Here are a handful. First, this study uses the susceptibility PGS, and if it works reasonably well, then there is every likelihood that a better PGS developed to predict progression will do even better. So, this study motivates genome-wide association studies on progression. Similarly, is it possible to refine predictors independently for UC and CD? Other questions include how best to integrate PGS with biochemical, histological, radiological, pharmaceutical, and other data types. The molecular basis underlying the association between PGS and disease progression also remains unanswered. In CD it seems to relate to extent of disease, but that is not the case for UC.

From a clinical perspective, though, what is needed now is prospective research on whether or not patients wish to know their estimated risk of progression based on the PGS. Does someone in the lowest decile find some comfort in knowing that their likelihood of progressing to colectomy is only 15%, or conversely, do patients in the top decile become depressed learning their prognosis is poor? Or does this help physicians prepare for a high likelihood of progression? Or relatedly, does inclusion of this information alter the modality of treatment (specifically, early use of biologics), and does that improve outcomes while containing costs? For this, a randomized clinical trial is needed.

Is there anything else you'd like to say about this work?

Dr. Gibson: All that genetics can do is improve the odds or bias the patient to the most appropriate therapeutic option(s). That is no different from standard medical practice, but this information is potentially powerful. The authors are not saying that you can predict disease course; they are saying that some people are more likely to progress to severe disease than others and we can see that at diagnosis. If this knowledge improves the outcome for even a quarter of patients, or prevents unnecessary biologic usage and contains costs for example, then it is a win for medical care in general, without being a precise answer for any individual patient.

Dr. Gibson reported having no relevant disclosures.