Transcript
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Welcome to CE on ReachMD. This activity is provided by Global Learning Collaborative and is part of our IBD Masterclass curriculum.
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Dr. Dolinger:
Hello. I'm Michael Dolinger. In this episode, we're taking a closer look at genetic susceptibility in inflammatory bowel disease. While the gut microbiome and environment receive a lot of attention, to further our understanding of IBD, we have to turn to the realm of genomics.
Having a first-degree relative with IBD is one of the strongest known risk factors for developing the disease. IBD occurs more frequently among individuals with affected family members, nearly 8 times more often for Crohn's disease and 4 times more often for ulcerative colitis in first-degree relatives. The risk is also elevated, though to a lesser extent, in second- and third-degree relatives.
The highest risk of developing IBD occurs early in life, especially in those less than 20 years of age.
Genetics explain only a portion of IBD risk. These variants account for roughly 8 to 13% of disease variants in Crohn's disease and about 4 to 7% in ulcerative colitis.
When we think about genetic variants, we want to think about it with monogenic and polygenic risks at the forefront of our mind. When we think about monogenic IBD, monogenic IBD is caused by a single, highly penetrant genetic mutation that disrupts key immune or epithelial pathways involved in intestinal homeostasis. It is rare and follows Mendelian inheritance but occurs more frequently in very early-onset IBD, or VEO-IBD, which is particularly in children diagnosed less than 6 years of age and even more common in children diagnosed under the age of 3 years. It often presents with more severe disease, extraintestinal manifestations or unusual and opportunistic infections.
Because the underlying defects affect a specific pathway, treatment may require mechanism-based therapies or hematopoietic stem cell transplantation rather than conventional IBD treatments. Therefore, in children under the age of 6, you always want to make sure that you genetically test them. There are several comprehensive immune deficiency panels and other monogenic IBD panels that are commercially available around the country.
In contrast, polygenic IBD, which accounts for the majority of cases, results from the combined effects of hundreds of common genetic variants, each contributing a small increase in risk. These variants interact with environmental factors and the gut microbiome to drive chronic intestinal inflammation.
Unlike monogenic disease, polygenic IBD activity typically presents in adolescence or adulthood and is managed using standard therapies such as biologics or small-molecule agents.
If you have a young adult who is not responding to these conventional agents, it's important to think that they may have a monogenic IBD that has actually been missed and it should have been diagnosed earlier and should be tested for.
From a mechanistic standpoint, most genetic variants fall into several key biological pathways that are critical for maintaining intestinal homeostasis.
Let's start with the innate immunity and bacterial recognition pathways. The best-known gene here is NOD2. This was the first IBD susceptibility gene identified and still remains strongly associated with Crohn's disease. NOD2 encodes an intracellular receptor that recognizes bacterial components in the gut. Mutations in NOD2 are associated with ileal disease and more aggressive Crohn's phenotypes, including stricturing and penetrating complications.
A second pathway involves autophagy. This is where the intracellular process of clearing pathogens occurs. Genes such as ATG16L1 and IRGM regulate this pathway, and disruption can impair Paneth cell function and antimicrobial peptide secretion, weakening mucosal defenses against gut microbes.
Another major category involves epithelial barrier integrity. Genes affecting tight junctions and epithelial function lead to increase in intestinal permeability. And interestingly, studies suggest that this barrier dysfunction may precede clinical disease, highlighting its central role in IBD pathogenesis and its new role in IBD prevention studies.
Lastly, many susceptibility genes affect immune signaling pathways, particularly what we know now as the IL-23 and Th17 axis. Variants in genes such as IL23R, IL12B, and STAT3 have strong associations with both Crohn's disease and ulcerative colitis. Importantly, this pathway has become a major therapeutic target in IBD.
In summary, we have really strong associations of genes—NOD2, autophagy genes, and barrier function—in Crohn's disease, and in ulcerative colitis we also have a strong gene association with the major histocompatibility complex, MHC region, on chromosome 6.
In fact, one of the most important ways genetics has influenced critical care is by informing targeted therapies. For example, knowledge that IL-23 signaling pathways play a central role in disease pathogenesis has helped drive development of the new IL-23 selective inhibitors, including agents like risankizumab, guselkumab, and mirikizumab.
Similarly, the identification of cytokine signaling pathways involved in inflammation has led to the development of JAK inhibitors, which block signaling from multiple inflammatory cytokines that are implicated in IBD.
So how does knowledge of genetic variants help predict treatment response and guide personalized therapy?
We know that it plays a role in treatment decisions. Clinical implementation of genetics is limited, but we have TPMT and NUDT15 genotyping that can predict thiopurine-induced myelosuppression with high accuracy, and pretreatment testing is recommended in multiple guidelines.
TPMT abnormalities affect 25% of European patients who develop myelosuppression. And similarly, NUDT15 affects East Asian, Latin American and South Asian populations disproportionately. Genotype-based dosing reduces hematologic adverse events by approximately 29%, with the benefit attributed to NUDT15 testing in Asian populations.
We also know that NOD2 may correlate with stricturing and penetrating Crohn's disease and that anti-TNF therapy response has shown associations with multiple genetic variants, though the predictive accuracy remains moderate.
Currently, there is a lot of interest in polygenic risk scores and the prediction of disease severity and complications in IBD. A 2026 nationwide Danish study found that patients in the highest polygenic risk quintile had hazard ratio of 2.74 for major surgery in Crohn's disease and 2.04 in ulcerative colitis compared to the lowest quintile.
Higher genetic burden is associated with elevated inflammatory markers, fecal calprotectin, CRP, lower hemoglobin, and increased need for corticosteroids, immunomodulators, and biologics.
In Crohn's disease specifically, increasing genetic burden predicts earlier age of diagnosis, 5 years earlier in the highest quintile versus the lowest quintile, ileal involvement and fibrostenotic disease requiring ileal resection.
Lastly, transcriptional risk scores, which are based on gene expression profiling, outperform standard genetic risk scores, with transcriptional risk assessment achieving nearly 50% positive predictive value for colectomy in ulcerative colitis, for example. However, these risk scores are not yet validated and remain to infiltrate clinical practice. They may have future implications in predicting colectomy and treatment response in ulcerative colitis, as well as treatment response in Crohn's disease. However, these current genetic risk scores overall only explain 8 to 13% of disease variants in Crohn's disease and 4 to 7% in ulcerative colitis, really further limiting their clinical utility for individual patient prediction.
Although multiple genetic markers correlate with treatment response and disease severity, predictive accuracy remains limited and routine genetic-guided treatment is not yet standard.
To wrap up, IBD is clearly a multifactorial disease, with genetics laying the groundwork for susceptibility. Thanks for joining me for this bite-sized episode.
Announcer:
You have been listening to CE on ReachMD. This activity is provided by Global Learning Collaborative and is part of our IBD Masterclass curriculum.
To receive your free CE credit, or to download this activity, go to ReachMD.com/CME. Thank you for listening.
In support of improving patient care, Global Learning Collaborative (GLC) and Chron’s Colitis Foundation is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team. 
Global Learning Collaborative designates this activity for 1.0 contact hour(s)/0.1 CEUs of pharmacy contact hour(s). 
Global Learning Collaborative has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit(s) for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit(s). Approval is valid until 05.01.27. PAs should claim only the credit commensurate with the extent of their participation in the activity. 
