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Genome wide association (GWA) predictors of anti-TNFα therapeutic responsiveness in pediatric inflammatory bowel disease

Dubinsky, Marla C. MD1,*; Mei, Ling1; Friedman, Madison1; Dhere, Tanvi MD2; Haritunians, Talin1; Hakonarson, Hakon3; Kim, Cecilia3; Glessner, Joseph3; Targan, Stephan R. MD1; McGovern, Dermot P. MD1; Taylor, Kent D.1; Rotter, Jerome I. MD1

doi: 10.1002/ibd.21174
Original Clinical Articles: GWA Predictors of Anti-TNFa: Original Article

Background: Interindividual variation in response to anti-TNFα therapy may be explained by genetic variability in disease pathogenesis or mechanism of action. Recent genome-wide association studies (GWAS) in inflammatory bowel disease (IBD) have increased our understanding of the genetic susceptibility to IBD. The aim was to test associations of known IBD susceptibility loci and novel “pharmacogenetic” GWAS identified loci with primary nonresponse to anti-TNFα in pediatric IBD patients and develop a predictive model of primary nonresponse.

Methods: Primary nonresponse was defined using the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and partial Mayo score for ulcerative colitis (UC). Genotyping was performed using the Illumina Infinium platform. Chi-square analysis tested associations of phenotype and genotype with primary nonresponse. Genetic associations were identified by testing known IBD susceptibility loci and by performing a GWAS for primary nonresponse. Stepwise multiple logistic regression was performed to build predictive models.

Results: Nonresponse occurred in 22 of 94 subjects. Six known susceptibility loci were associated with primary nonresponse (P < 0.05). Only the 21q22.2/BRWDI loci remained significant in the predictive model. The most predictive model included 3 novel “pharmacogenetic” GWAS loci, the previously identified BRWD1, pANCA, and a UC diagnosis (R2 = 0.82 and area under the curve [AUC] = 0.98%). The relative risk of nonresponse increased 15-fold when number of risk factors increased from 0–2 to ≥3.

Conclusions: The combination of phenotype and genotype is most predictive of primary nonresponse to anti-TNFα in pediatric IBD. Defining predictors of response to anti-TNFα may allow the identification of patients who will not benefit from this class of therapy. Inflamm Bowel Dis 2010

1Department of Pediatrics and Medicine, Inflammatory Bowel Disease Program, Medical Genetics Institute, Cedars Sinai Medical Center, Los Angeles, California

2Department of Medicine, Emory University, Atlanta, Georgia

3Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

*Reprints: 8635 West 3rd St., Ste. 1165W, Los Angeles, CA 90048

Email: Marla.dubinsky@cshs.org

Received for publication 15 October 2009; Accepted 15 October 2009.

Published online 10 December 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: NIH/NIDDK; Grant Number: P01-DK046763; Grant sponsor: Cedars-Sinai Medical Center Inflammatory Bowel/Immunobiology Institute Research Funds; Grant sponsor: Feintech Family Chair in IBD (SRT); Grant sponsor: Cedars-Sinai Board of Governors' Chair in Medical Genetics (JIR); Grant sponsor: Abe and Claire Levine Chair in Pediatric IBD (MD); Grant sponsor: NCRR; Grant Number: M01-RR00425 (GCRC); Grant sponsor: DERC; Grant Number: DK063491; Grant sponsor: Centocor and UCB pharma.

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