Computational drug repositioning of atorvastatin for ulcerative colitis

Author:

Bai Lawrence123ORCID,Scott Madeleine K D234,Steinberg Ethan5,Kalesinskas Laurynas6,Habtezion Aida127,Shah Nigam H3ORCID,Khatri Purvesh23ORCID

Affiliation:

1. Immunology Program, Stanford University School of Medicine, Stanford, California, USA

2. Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA

3. Center for Biomedical Informatics Research, Department of Medicine, Stanford University, Stanford, California, USA

4. Biophysics Program, Stanford University School of Medicine, Stanford, California, USA

5. Computer Science Program, Department of Computer Science, Stanford University, Stanford, California, USA

6. Biomedical Informatics Training Program, Stanford University School of Medicine, Stanford, California, USA

7. Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

Abstract

Abstract Objective Ulcerative colitis (UC) is a chronic inflammatory disorder with limited effective therapeutic options for long-term treatment and disease maintenance. We hypothesized that a multi-cohort analysis of independent cohorts representing real-world heterogeneity of UC would identify a robust transcriptomic signature to improve identification of FDA-approved drugs that can be repurposed to treat patients with UC. Materials and Methods We performed a multi-cohort analysis of 272 colon biopsy transcriptome samples across 11 publicly available datasets to identify a robust UC disease gene signature. We compared the gene signature to in vitro transcriptomic profiles induced by 781 FDA-approved drugs to identify potential drug targets. We used a retrospective cohort study design modeled after a target trial to evaluate the protective effect of predicted drugs on colectomy risk in patients with UC from the Stanford Research Repository (STARR) database and Optum Clinformatics DataMart. Results Atorvastatin treatment had the highest inverse-correlation with the UC gene signature among non-oncolytic FDA-approved therapies. In both STARR (n = 827) and Optum (n = 7821), atorvastatin intake was significantly associated with a decreased risk of colectomy, a marker of treatment-refractory disease, compared to patients prescribed a comparator drug (STARR: HR = 0.47, P = .03; Optum: HR = 0.66, P = .03), irrespective of age and length of atorvastatin treatment. Discussion & Conclusion These findings suggest that atorvastatin may serve as a novel therapeutic option for ameliorating disease in patients with UC. Importantly, we provide a systematic framework for integrating publicly available heterogeneous molecular data with clinical data at a large scale to repurpose existing FDA-approved drugs for a wide range of human diseases.

Funder

Stanford Bio-X Graduate Fellowship

National Heart, Lung, and Blood Institute

The Stanford University Medical Scientist Training Program

Bill and Melinda Gates Foundation

National Institute of Allergy and Infectious Diseases

Department of Defense

Ralph & Marian Falk Medical Research Trust

Publisher

Oxford University Press (OUP)

Subject

Health Informatics

Reference84 articles.

1. Ulcerative colitis;Ungaro;J Gastroenterol,2018

2. Inflammatory bowel disease;Abraham;N Engl J Med,2009

3. ACG clinical guideline: ulcerative colitis in adults;Rubin;Am J Gastroenterol,2019

4. Management of acute severe ulcerative colitis;Kedia;World J Gastrointest Pathophysiol,2014

5. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis;Ford;Am J Gastroenterol,2011

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