Multidimensional Prognostic Risk Assessment Identifies Association Between IL12B Variation and Surgery in Crohn's Disease

• Type of Material: Article
• Authors: Marla C. Dubinsky, Cedars Sinai Medical Center; Subramaniam Kugathasan, Emory University; Soonil Kwon, Cedars Sinai Medical Center; Talin Haritunians, Cedars Sinai Medical Center; Iwona Wrobel, Alberta Children’s Hospital; Ghassan Wahbeh, Seattle Children's Hospital; Antonio Quiros, California Pacific Medical Center; Ron Bahar, Cedars Sinai Medical Center; Gary Silber, Phoenix Children's Hospital; Sharmayne Farrior, Cedars Sinai Medical Center; Michael Stephens, Medical College of Wisconsin; Nick Teleten, Cedars Sinai Medical Center; Deepa Panikkath, Cedars Sinai Medical Center; Andrew Ippoliti, Cedars Sinai Medical Center; Eric Vasiliauskas, Cedars Sinai Medical Center; Phillip Fleshner, Cedars Sinai Medical Center; Chadwick Williams, Cedars Sinai Medical Center; Carol Landers, Cedars Sinai Medical Center; Jerome I. Rotter, Cedars Sinai Medical Center; Stephan R. Targan, Cedars Sinai Medical Center; Kent D. Taylor, Cedars Sinai Medical Center; Dermont P. B McGovern, Cedars Sinai Medical Center
• Language: English
• Date: 2013-07-01
• Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B - CC-BY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2013 Crohn's & Colitis Foundation of America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1097/MIB.0b013e318281f275
• Title of Journal or Parent Work: Inflammatory Bowel Diseases
• ISSN: 1078-0998
• Volume: 19
• Issue: 8
• Start Page: 1662
• End Page: 1670
• Grant/Funding Information: Additional support was received from The Leona M. and Harry B. Helmsley Charitable Trust; This study was supported in part by NIH/NIDDK grant P01-DK046763; Cedars-Sinai Medical Center Inflammatory Bowel/ Immunobiology Institute Research Funds; The Feintech Family Chair in IBD (SRT); The Cedars-Sinai Board of Governors’ Chair in Medical Genetics (JIR); The Abe and Claire Levine Chair in Pediatric IBD (MD); Joshua L and Lisa Z. Greer Chair in IBD Genetics (DPBM); DK062413 (DPBM); CTSI Grant UL1RR033176; and DERC grant DK063491.
• Keywords: COMPLICATIONS; GENOME-WIDE ASSOCIATION; Life Sciences & Biomedicine; Gastroenterology & Hepatology; SEROLOGICAL MARKERS; NOD2/CARD15 GENOTYPE; clinical phenotype; genotype; CHILDREN; surgery for IBD; INFLAMMATORY-BOWEL-DISEASE; SUSCEPTIBILITY LOCI; NEED; BEHAVIOR; Science & Technology; complications of IBD; biomarkers; ONSET
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery

Abstract

Background: The ability to identify patients with Crohn's disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genomewide association studies have identified multiple IBD loci with unknown phenotypic consequences. The aims of this study were to: (1) identify associations between known and novel CD loci with early resective CD surgery and (2) develop the best predictive model for time to surgery using a combination of phenotypic, serologic, and genetic variables. Methods: Genotyping was performed on 1,115 subjects using Illumina-based genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n = 71) and by performing a genomewide association study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery. Results: Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, and C11orf30). Genome-wide association identified novel putative loci associated with early surgery: 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups. Conclusions: Progression to surgery is faster in patients with CD with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway.