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Thiopurine Effectiveness in Patients with Crohn's Disease: A Study of Genetic and Clinical Predictive Factors

Koifman, Eduard MD*; Karban, Amir MD*,†; Mazor, Yoav MD*; Chermesh, Irit MD*,†; Waterman, Matti MD*,†; Almog, Ronit MD, PhD; Ben-Horin, Shomron MD§; Eliakim, Rami MD§; Krivoy, Norberto MD†,‖; Efrati, Edna PhD‖,¶; Chowers, Yehuda MD*,†

doi: 10.1097/MIB.0b013e31828828d3
Original Clinical Articles

Background: Thiopurines are efficacious in the treatment of Crohn's disease and were recently shown to induce T-cell apoptosis by modulation of Rac1 activation. To assess whether polymorphisms in Rac1 and other apoptosis-related genes, combined with clinical parameters, can predict response to thiopurines.

Methods: A retrospective cohort of 156 thiopurine-treated patients with Crohn's disease was genotyped for 11 single-nucleotide polymorphisms (SNPs): 9 SNPs in Rac1, 1 SNP in the Fas ligand −843 T>C, and 1 SNP in the Caspase-9 93 C>T. Clinical data were extracted from the medical charts. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between demographic, clinical, and genetic variables and thiopurine response rates were calculated.

Results: The overall response rate to thiopurines was 74% (115/156). The Rac1 SNP rs34932801 heterozygote genotype GC was associated with a lower response rate compared with the wild-type GG genotype (46% versus 76%; OR = 0.26; 95% CI, 0.08–0.91; P = 0.036). Only wild-type homozygotes were found for 5 Rac1 SNPs. None of the other 3 Rac1 SNPs were associated with response to thiopurines. Patients with Montreal B3 behavior pattern responded worse than those with a B1 behavior pattern (59%, versus 80%; OR = 0.37; 95% CI, 0.17–0.83; P = 0.016). Sephardic Jews had a lower response rate to thiopurines compared with Jews of Ashkenazi or mixed ancestry (60% versus 82%; OR = 0.32; 95% CI, 0.15–0.69, P = 0.003).

Conclusions: Rac1 SNP rs34932801carriage, Montreal B3 disease behavior, and a Sephardic Jewish origin were associated with unfavorable response to thiopurines. Corroboration of these associations in larger cohorts is warranted.

Article first published online 10 May 2013

*Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel;

Rappaport Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, Israel;

School of Public Health, University of Haifa, Haifa, Israel;

§Department of Gastroenterology, Chaim Sheba Medical Center, Tel-Hashomer and Sackler Medical School, Tel-Aviv University, Tel-Aviv, Israel;

Clinical Pharmacology Institute, Rambam Health Care Campus, Haifa, Israel; and

Rappaport-Rambam Center for Translational Genetics, Rappaport Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa, Israel.

Reprints: Eduard Koifman, MD, Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel (e-mail: e_koifman@rambam.health.gov.il).

Supported partially by the Newell Foundation Research Fund on the Genetic Studies of Inflammatory Bowel Diseases in Israel (Newell Foundation-10707).

S. Ben-Horin and Y. Chowers have served as consultants to Abbot and Schering-Plough and have received unrestricted educational grant from Janssen.

Eduard Koifman and Amir Karban shared first authorship.

Edna Efrati and Yehuda Chowers shared senior authorship.

Received December 28, 2012

Accepted January 16, 2013

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