Stratification of Risk of Progression to Colectomy in Ulcerative Colitis using Measured and Predicted Gene Expression

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of ulcerative colitis (UC) patients require colectomy within five years of diagnosis, but polygenic risk scores (PRS) utilizing findings from GWAS are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn’s disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a Transcriptional Risk Score (TRS). Here we demonstrate that both measured (TRS) and polygenic predicted gene expression (PPTRS) identify UC patients at 5-fold elevated risk of colectomy with data from the PROTECT clinical trial and UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with transcriptome-wide association studies to stratify risk of disease complications. ### Competing Interest Statement JSH has served on an advisory board for Janssen and is acting as a consultant for AbbVie, Takeda, Lilly, Boehringer-Ingelheim, Allergan, Pfizer, Receptos, and AstraZeneca. SDT has been a member of an independent data monitoring committee for Lycera Corporation. AMG has received research support from AbbVie; been a consultant for AbbVie, Celgene, Janssen, Lilly, Pfizer, and Takeda; and been a speaker for AbbVie, Janssen, and Shire. NSL has been a consultant for AbbVie. CGS has been a consultant for AbbVie. JM has been a consultant for Janssen, Celgene, and Lilly. JRR has been a consultant for AbbVie, Celgene, Janssen, Luitpold, and Pfizer, and received grant funding from Janssen and AbbVie. ASP has participated in speakers bureaus AbbVie and Janssen. MBH has received research grants from Genentech, AbbVie, Shire, Takeda, Mallinkrodt, Janssen, and Gilead. PAR has been a consultant for Shire and Leutpold; been a speaker for AbbVie; and received research support from TechLab. SK has been a consultant for Janssen and UCB. LAD has received grant support from AbbVie and Janssen. DPBM and TH are faculty members at Cedars-Sinai Medical Center. EM is an employees at Cedars-Sinai. Cedars-Sinai has financial interests in Prometheus Biosciences, Inc., a company which has access to the data and specimens in Cedars-Sinai MIRIAD Biobank. Prometheus Biosciences, Inc. seeks to develop commercial products. DM is a paid consultant and shareholder of Prometheus Biosciences, Inc. DM has consulted for Pfizer, Gilead, Palatin Technologies, Bridge Biotherapeutics, and Takeda. All other authors declare no competing interests.