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Combination of genetic and quantitative serological immune markers are associated with complicated Crohn's disease behavior

Lichtenstein, Gary R. MD1,*; Targan, Stephan R. MD2,3; Dubinsky, Marla C. MD3,4; Rotter, Jerome I. MD2,5; Barken, Derren M. PhD6; Princen, Fred PhD6; Carroll, Susan PhD6; Brown, Michelle BA6; Stachelski, Jordan BS6; Chuang, Emil MD6; Landers, Carol J. BS2,3; Stempak, Joanne M. MS7; Singh, Sharat PhD6; Silverberg, Mark S. MD, PhD7

doi: 10.1002/ibd.21661
Original Article

Background: Treatment of Crohn's disease (CD) with biologics may alter disease progression, leading to fewer disease-related complications, but cost and adverse event profiles often limit their effective use. Tools identifying patients at high risk of complications, who would benefit the most from biologics, would be valuable. Previous studies suggest that biomarkers may aid in determining the course of CD. We aimed to determine if combined serologic immune responses and NOD2 genetic markers are associated with CD complications.

Methods: In this cross-sectional study, banked blood from well-characterized CD patients (n = 593; mean follow-up: 12 years) from tertiary and community centers was analyzed for six serological biomarkers (ASCA-IgA, ASCA-IgG, anti-OmpC, anti-CBir1, anti-I2, pANCA). In a patient subset (n = 385), NOD2 (SNP8, SNP12, SNP13) genotyping was performed. Complications included stricturing and penetrating disease behaviors. A logistic regression model for the risk of complications over time was constructed and evaluated by cross-validation.

Results: For each serologic marker, complication rates were stratified by quartile. Complication frequency was significantly different across quartiles for each marker (P trend ≤ 0.001). Patients with SNP13 NOD2 risk alleles experienced increased complications versus patients without NOD2 mutations (P ≤ 0.001). A calibration plot of modeled versus observed complication rates demonstrated good agreement (R = 0.973). Performance of the model integrating serologic and genetic markers was demonstrated by area under the receiver operating characteristic curve (AUC = 0.801; 95% confidence interval: 0.757–0.846).

Conclusions: This model combining serologic and NOD2 genetic markers may provide physicians with a tool to assess the probability of patients developing a complication over the course of CD.

1 Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania

2 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California

3 Cedars-Sinai Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California

4 Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California

5 Cedars-Sinai Medical Genetics Institute, Los Angeles, California

6 Research and Development, Prometheus Laboratories Inc., San Diego, California

7 Mount Sinai Hospital IBD Group, Zane Cohen Centre for Digestive Diseases, University of Toronto, Toronto, Ontario, Canada

*Reprints: Professor of Medicine, Director, Center for Inflammatory Bowel Disease, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Division of Gastroenterology, Department of Medicine, 3rd Floor Ravdin Building, 3400 Spruce St., Philadelphia, PA 19104-4283


Received 12 November 2010; Accepted 15 December 2010

Published online 9 March 2011 in Wiley Online Library (

Grant sponsor: Prometheus Laboratories Inc, San Diego, CA.

Disclosures: Dr. Barken, Dr. Princen, Dr. Carroll, Shelly Brown, Jordan Stachelski, Dr. Chuang, and Sharat Singh are employees of Prometheus Laboratories Inc. Carol Landers is a stockholder of Prometheus Laboratories Inc. Dr. Rotter and Joanne Stempak have nothing to disclose. Dr. Lichtenstein has received consulting fees and research support from Prometheus Laboratories Inc. Dr. Targan is a founder and stockholder of PrometheusLaboratories Inc. Dr. Dubinsky is a consultant for Prometheus Laboratories Inc. Dr. Silverberg has received consulting fees and research support from Prometheus Laboratories Inc. Writing assistance: Dr. Anthony Stonehouse provided extensive writing support during the development of this article. Dr. Stonehouse is an employee of Watson & Stonehouse Enterprises, LLC.

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