Genetic Risk May Predict Thromboembolic Disease in Inflammatory Bowel Disease

Thromboembolic disease risk in people with inflammatory bowel disease may be influenced by patient genetics, including polygenic risk scores.

Study data published in Gastroenterology confirm the genetic risk component of thromboembolic disease (TED) in patients with inflammatory bowel disease (IBD). In a genotyping study of patients with IBD, those with high TED polygenic risk scores were significantly more likely to have TED events than their counterparts with low polygenic risk scores.

Investigators extracted data from the Inflammatory Bowel Disease Genetics Consortium, which performs genotyping on samples from people with IBD around the world. For the present study, samples from cases recruited at Cedars-Sinai Medical Center were used in analyses. Only cases with both whole genome genotyping and whole exome sequencing data were included. Polygenic risk scores were generated for these individuals using data from the Illumina Global Screening Array, which comprises genetic information from 2600 controls and 8984 patients with IBD. Thrombophilia pathogenic variants were identified from whole exome sequencing data.

Patients were considered to have genetically high risk for TED if they had a high TED polygenic risk scores and carried at least 1 thrombophilia pathogenic variant. Logistic regression was used to assess the association between genetic TED risk and likelihood of TED event.

Of 792 patients with IBD, 49 had a high polygenic risk score and 82 carried at least 1 thrombophilia pathogenic variant. Overall, 122 patients (15.4%) were determined to have genetically high risk for TED. Among 715 patients with documented TED status available, 63 (8.8%) experienced TED events.

Patients with a documented TED event had significantly longer IBD duration (23.7 vs 19.8 years; P =.034), were older at IBD onset (30.1 vs 23.7 years; P =.00075), and were more likely to have had IBD-related surgery (odds ratio [OR], 2.36; P =.0045) compared with patients without a documented TED event.

After adjustments for age, disease duration, and surgical history, genetic TED risk was significantly associated with increased odds of TED event (OR, 2.5; P =.0036). Both high polygenic risk score (OR, 3.13; P =.0070) and carriage of at least 1 thrombophilia pathogenic variant (OR, 2.11; P =.0042) were independently associated with TED.

Monogenic and polygenic risk appeared to have an additive effect on TED risk; patients with both high polygenic risk scores and pathogenic variants had the highest TED risk (P =.0048). The next-highest risk category included patients with just 1 risk factor; the lowest risk category included patients with neither high polygenic risk scores nor thrombophilia pathogenic variant carriage. Among patients with just 1 risk factor, those with polygenic risk scores had marginally higher risk than patients with thrombophilia pathogenic variants only.

Those with high genetic risk more often had thrombosis at multiple sites compared to those with low genetic risk (78% vs 42%; OR, 3.96; P =.048). Patients with high TED genetic risk were also more likely to have received biologics (71% vs 37%; OR, 3.95; P =.024) than patients without genetic risk.

The primary study limitation was cohort homogeneity; only patients with European ancestry were included due to the genetic makeup of the Global Screening Array cohort. As with other genotyping studies, data on patients of non-European ancestry is lacking. Further study is necessary to extrapolate TED risk in patients of non-European ancestry.

“[W]e have demonstrated that [approximately] 1 in 7 IBD patients are genetically at a higher risk for TED, and genetic risk is independently associated with TED events when adjusting for time-dependent parameters and IBD-related surgery,” the investigators concluded. “[O]ur findings suggest that strategies for managing patients at high risk of TED identified through genetic approaches should be developed.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Naito T, Botwin GJ, Haritunians T, et al. Prevalence and effect of genetic risk of thrombo-embolic disease in inflammatory bowel disease. Published online October 21, 2020. Gastroenterology. doi: 10.1053/j.gastro.2020.10.019