Genetic Risk of Inflammatory Bowel Disease Is Associated With Disease Course Severity.

Area of Science:

• Genetics
• Gastroenterology
• Immunology

Background:

• Genetic susceptibility to inflammatory bowel disease (IBD) is well-researched, but its role in disease progression is less understood.
• Investigating the genetic contribution to IBD severity is crucial for understanding disease heterogeneity.

Purpose of the Study:

• To explore the association between genetic susceptibility to IBD and disease severity in a large Danish cohort.
• To determine if genetic predisposition influences inflammatory markers, hospitalizations, surgeries, and medication use.

Main Methods:

• Polygenic risk scores (PGS) for IBD were calculated for 3732 Crohn's disease (CD) and 4535 ulcerative colitis (UC) patients.
• Associations between PGS and disease outcomes (inflammatory markers, surgery, medication) were analyzed.
• The role of disease extent as a mediator was evaluated.

Main Results:

• Higher PGS correlated with increased inflammatory markers (fecal calprotectin, C-reactive protein) and decreased hemoglobin.
• Elevated PGS significantly increased the risk of major surgery in both CD (HR=2.74) and UC (HR=2.04).
• Severe disease was strongly associated with higher PGS in both CD and UC, indicating a genetic link to disease severity and treatment needs.

Conclusions:

• Higher genetic susceptibility for IBD is linked to a more severe disease course.
• Disease extent mediates this association in CD but not UC, suggesting shared genetic factors for susceptibility and severity in UC.