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Multidimensional Prognostic Risk Assessment Identifies Association Between IL12B Variation and Surgery in Crohns Disease

Dubinsky, Marla C. MD*; Kugathasan, Subra MD; Kwon, Soonil PhD; Haritunians, Talin PhD; Wrobel, Iwona MD§; Wahbeh, Ghassan MD; Quiros, Antonio MD; Bahar, Ron MD*; Silber, Gary MD**; Farrior, Sharmayne RN*; Stephens, Michael MD††; Teleten, Nick‡‡; Panikkath, Deepa‡‡; Ippoliti, Andrew MD‡‡; Vasiliauskas, Eric MD‡‡; Fleshner, Phillip MD§§; Williams, Chadwick MD‡‡; Landers, Carol‡‡; Rotter, Jerome I. MD; Targan, Stephan R. MD‡‡; Taylor, Kent D. PhD; McGovern, Dermot P. B. MD, PhD‡,‡‡

Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0b013e318281f275
Original Clinical Articles
Abstract

Background: The ability to identify patients with Crohn’s disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide 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 genome-wide 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.

In Brief

Article first published online 9 May 2013

Author Information

*Departments of Pediatrics, Pediatric Inflammatory Bowel Disease Center and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California;

Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia;

Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California;

§Department of Pediatrics, Alberta Children’s Hospital, Calgary Alberta, Canada;

Department of Pediatrics, Seattle Children’s Hospital, Seattle, Washington;

Department of Pediatrics, California Pacific Medical Center, San Francisco, California;

**Department of Pediatrics, Phoenix Children’s Hospital, Phoenix, Arizona;

††Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin;

‡‡F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; and

§§Department of Colorectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California.

Reprints: Marla C. Dubinsky, MD, 8635 West 3rd Street, Suite 1165W, Los Angeles, CA 90048 (e-mail: dubinskym@csmc.edu).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

Supported in part by the National Institutes of Health/National institute of Digestive Diseases and Kidney (NIDDK) grant P01-DK046763; Cedars-Sinai Medical Center Inflammatory Bowel/Immunobiology Institute Research Funds; The Feintech Family Chair in IBD (S.R.T.); The Cedars-Sinai Board of Governors’ Chair in Medical Genetics (J.I.R.); The Abe and Claire Levine Chair in Pediatric IBD (M.D.), Joshua L and Lisa Z. Greer Chair in IBD Genetics (D.P.B.M.), DK062413 (D.P.B.M.), CTSI Grant UL1RR033176 and DERC grant DK063491. Additional support was received from The Leona M. and Harry B. Helmsley Charitable Trust.

The authors have no conflicts of interest to disclose.

M. C. Dubinsky is a consultant for Prometheus Laboratories.

Received November 28, 2012

Accepted November 29, 2012

© Crohn's & Colitis Foundation of America, Inc.

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