Gastroenterology. 2020 Oct 19;S0016-5085(20)35276-8. doi: 10.1053/j.gastro.2020.10.019.Online ahead of print.

Takeo Naito ¹, Gregory J Botwin ², Talin Haritunians ², Dalin Li ², Shaohong Yang ², Michelle Khrom ², Jonathan Braun ², NIDDK IBD Genetics Consortium; Lisa Abbou ², Emebet Mengesha ², Christine Stevens ³, Atsushi Masamune ⁴, Mark Daly ³, Dermot P B McGovern ⁵

Author information

• ¹F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
• ²F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
• ³Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
• ⁴Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
• ⁵F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: dermot.mcgovern@cshs.org.

Abstract

Background and aims: The largest cause of mortality in patients with inflammatory bowel disease (IBD) remains thrombo-embolic disease (TED). Recent reports have demonstrated that both monogenic and polygenic factors contribute to TED and 10% of 'healthy' subjects are genetically at high risk for TED. Our aim was to utilize whole exome sequencing (WES) and genome-wide genotyping to determine the proportion of IBD patients genetically at risk for TED and investigate the effect of genetic risk of TED in IBD.

Methods: The TED polygenic risk score (PRS) was calculated from genome-wide genotyping. Thrombophilia pathogenic variants (TPV) were extracted from WES. In total, 792 IBD patients had both WES and genotyping data. We defined patients at genetically high risk for TED if they had a high TED PRS or carried at least one TPV.

Results: We identified 122 out of 792 IBD patients (15.4%) as genetically high risk for TED. Among 715 out of 792 subjects whose documented TED status were available, 63 of the 715 patients (8.8 %) had TED events. Genetic TED risk was significantly associated with increased TED event (OR = 2.5, P = 0.0036). Additionally, we confirmed an additive effect of monogenic and polygenic risk on TED (P = 0.0048). Patients with high TED genetic risk more frequently had thrombosis at multiple sites (78 % vs 42 %, OR = 3.96, P = 0.048).

Conclusions: Genetic risk (both poly- and monogenic) was significantly associated with TED history. Our results suggest that genetic traits identify ∼1 in 7 IBD patients who will experience 2.5-fold or greater risk for TED.