Dataset Information

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

ABSTRACT: An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn 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 a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the 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 TWASs for stratification of risk of disease complications.

SUBMITTER: Mo A

PROVIDER: S-EPMC8456180 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

Mo Angela A Nagpal Sini S Gettler Kyle K Haritunians Talin T Giri Mamta M Haberman Yael Y Karns Rebekah R Prince Jarod J Arafat Dalia D Hsu Nai-Yun NY Chuang Ling-Shiang LS Argmann Carmen C Kasarskis Andrew A Suarez-Farinas Mayte M Gotman Nathan N Mengesha Emebet E Venkateswaran Suresh S Rufo Paul A PA Baker Susan S SS Sauer Cary G CG Markowitz James J Pfefferkorn Marian D MD Rosh Joel R JR Boyle Brendan M BM Mack David R DR Baldassano Robert N RN Shah Sapana S LeLeiko Neal S NS Heyman Melvin B MB Griffiths Anne M AM Patel Ashish S AS Noe Joshua D JD Davis Thomas Sonia S Aronow Bruce J BJ Walters Thomas D TD McGovern Dermot P B DPB Hyams Jeffrey S JS Kugathasan Subra S Cho Judy H JH Denson Lee A LA Gibson Greg G

American journal of human genetics 20210826 9

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of ris ...[more]

PMID: 34450030

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Project description:BackgroundDevelop a clinical and biological predictive model for colectomy risk in children newly diagnosed with ulcerative colitis (UC).MethodsThis was a multicenter inception cohort study of children (ages 4-17 years) newly diagnosed with UC treated with standardized initial regimens of mesalamine or corticosteroids (CS) depending upon initial disease severity. Therapy escalation to immunomodulators or infliximab was based on predetermined criteria. Patients were phenotyped by clinical activity per the Pediatric Ulcerative Colitis Activity Index (PUCAI), disease extent, endoscopic/histologic severity, and laboratory markers. In addition, RNA sequencing defined pretreatment rectal gene expression and high density DNA genotyping by the Affymetrix UK Biobank Axiom Array. Coprimary outcomes were colectomy over 3 years and time to colectomy. Generalized linear models, Cox proportional hazards multivariate regression modeling, and Kaplan-Meier plots were used.ResultsFour hundred twenty-eight patients (mean age 13 years) started initial theapy with mesalamine (n = 136), oral CS (n = 144), or intravenous CS (n = 148). Twenty-five (6%) underwent colectomy at ≤1 year, 33 (9%) at ≤2 years, and 35 (13%) at ≤3 years. Further, 32/35 patients who had colectomy failed infliximab. An initial PUCAI ≥ 65 was highly associated with colectomy (P = 0.0001). A logistic regression model predicting colectomy using the PUCAI, hemoglobin, and erythrocyte sedimentation rate had a receiver operating characteristic area under the curve of 0.78 (95% confidence interval [0.73, 0.84]). Addition of a pretreatment rectal gene expression panel reflecting activation of the innate immune system and response to external stimuli and bacteria to the clinical model improved the receiver operating characteristic area under the curve to 0.87 (95% confidence interval [0.82, 0.91]).ConclusionsA small group of children newly diagnosed with severe UC still require colectomy despite current therapies. Our gene signature observations suggest additional targets for management of those patients not responding to current medical therapies.

Project description:BackgroundIncreasing evidence supports immediate colectomy in acute fulminant ulcerative colitis in comparison with ongoing medical management. Prior studies have been limited to inpatient-only administrative data sets or single-institution experiences.ObjectiveThe purpose of this study was to compare outcomes of early versus delayed emergency colectomy in patients admitted with ulcerative colitis flares while controlling for known preoperative risks and acuity.DesignThis is a cohort study of patients undergoing emergent total abdominal colectomies for ulcerative colitis compared by the timing of surgery.SettingAdult patients undergoing an emergent total abdominal colectomy for ulcerative colitis, 2005 to 2015, were identified in the American College of Surgeons National Surgical Quality Improvement Program database.PatientsPatients undergoing total abdominal colectomy with an operative indication of ulcerative colitis admitted on a nonelective basis were selected.Main outcome measureThe primary outcomes measured were 30-day National Surgical Quality Improvement Program-reported mortality and postoperative complications, and early operation within 2 days of admission.ResultsWe identified 573 total abdominal colectomies after propensity score matching. Median time to surgery was 1 hospital day in the early group versus 6 hospital days in the delayed group (p < 0.001). Early operation was associated with a lower mortality rate (4.9% versus 20.3% in matched groups, p < 0.001) and lower complication rate (64.5% versus 72.0%, p = 0.052). Multivariable logistic regression with propensity weighting of mortality on preoperative risk factors demonstrated that early surgery is associated with an 82% decrease in the odds of death compared with delayed surgery (p < 0.001). Regression of morbidity on preoperative risk factors demonstrated that early surgery is associated with a 35% decrease in the odds of a complication with delayed surgery (p = 0.034).LimitationsQuality improvement data were used for clinical research questions.ConclusionsPatients undergoing immediate surgical intervention for acute ulcerative colitis have decreased postoperative complications and mortality rates. Rapid and early transitioning from medical to surgical management may benefit those expected to require surgery on the same admission. See Video Abstract at http://links.lww.com/DCR/A800.

Dataset Information

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

Publications

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

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