Takeo Naito1, Gregory J Botwin2, Talin Haritunians2, Dalin Li2, Shaohong Yang2, Michelle Khrom2, Jonathan Braun2, Lisa Abbou2, Emebet Mengesha2, Christine Stevens3, Atsushi Masamune4, Mark Daly3, Dermot P B McGovern5. 1. F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. 2. F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California. 3. Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts. 4. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. 5. F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: dermot.mcgovern@cshs.org.
Abstract
BACKGROUND AND AIMS: The largest cause of mortality in patients with inflammatory bowel disease (IBD) remains thromboembolic 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 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 was calculated from genome-wide genotyping. Thrombophilia pathogenic variants were extracted from whole-exome sequencing. In total, 792 IBD patients had both whole-exome sequencing and genotyping data. We defined patients at genetically high risk for TED if they had a high TED polygenic risk score or carried at least 1 thrombophilia pathogenic variant. RESULTS: We identified 122 of 792 IBD patients (15.4%) as genetically high risk for TED. Among 715 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 (odds ratio, 2.5; P = .0036). In addition, we confirmed an additive effect of monogenic and polygenic risk on TED (P = .0048). Patients with high TED genetic risk more frequently had thrombosis at multiple sites (78% vs 42%, odds ratio, 3.96; P = .048). CONCLUSIONS: Genetic risk (both poly- and monogenic) was significantly associated with TED history. Our results suggest that genetic traits identify approximately 1 in 7 patients with IBD who will experience 2.5-fold or greater risk for TED.
BACKGROUND AND AIMS: The largest cause of mortality in patients with inflammatory bowel disease (IBD) remains thromboembolic 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 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 was calculated from genome-wide genotyping. Thrombophilia pathogenic variants were extracted from whole-exome sequencing. In total, 792 IBD patients had both whole-exome sequencing and genotyping data. We defined patients at genetically high risk for TED if they had a high TED polygenic risk score or carried at least 1 thrombophilia pathogenic variant. RESULTS: We identified 122 of 792 IBD patients (15.4%) as genetically high risk for TED. Among 715 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 (odds ratio, 2.5; P = .0036). In addition, we confirmed an additive effect of monogenic and polygenic risk on TED (P = .0048). Patients with high TED genetic risk more frequently had thrombosis at multiple sites (78% vs 42%, odds ratio, 3.96; P = .048). CONCLUSIONS: Genetic risk (both poly- and monogenic) was significantly associated with TED history. Our results suggest that genetic traits identify approximately 1 in 7 patients with IBD who will experience 2.5-fold or greater risk for TED.
Authors: Angela Mo; Sini Nagpal; Kyle Gettler; Talin Haritunians; Mamta Giri; Yael Haberman; Rebekah Karns; Jarod Prince; Dalia Arafat; Nai-Yun Hsu; Ling-Shiang Chuang; Carmen Argmann; Andrew Kasarskis; Mayte Suarez-Farinas; Nathan Gotman; Emebet Mengesha; Suresh Venkateswaran; Paul A Rufo; Susan S Baker; Cary G Sauer; James Markowitz; Marian D Pfefferkorn; Joel R Rosh; Brendan M Boyle; David R Mack; Robert N Baldassano; Sapana Shah; Neal S LeLeiko; Melvin B Heyman; Anne M Griffiths; Ashish S Patel; Joshua D Noe; Sonia Davis Thomas; Bruce J Aronow; Thomas D Walters; Dermot P B McGovern; Jeffrey S Hyams; Subra Kugathasan; Judy H Cho; Lee A Denson; Greg Gibson Journal: Am J Hum Genet Date: 2021-08-26 Impact factor: 11.025
Authors: Arwa A Alodheilah; Omar A Alnujeidi; Nada A AlDhuwayhi; Maha M AlDhilan; Fatimah S Alsultan; Majd I Aldhuwayhi; Haya S Alnumayr; Fai M AlHotan; Shatha E Aljamaan Journal: Cureus Date: 2022-09-13