Prospective Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 21, 2017; 23(27): 4958-4967
Published online Jul 21, 2017. doi: 10.3748/wjg.v23.i27.4958
Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn’s disease
Uri Netz, Jane Victoria Carter, Maurice Robert Eichenberger, Gerald Wayne Dryden, Jianmin Pan, Shesh Nath Rai, Susan Galandiuk
Uri Netz, Jane Victoria Carter, Maurice Robert Eichenberger, Susan Galandiuk, Price Institute of Surgical Research, the Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, United States
Uri Netz, Department of Surgery A, Soroka University Medical Center, Beer Sheva 84101, Israel
Uri Netz, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
Gerald Wayne Dryden, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition University of Louisville School of Medicine Louisville, KY 40202, United States
Jianmin Pan, Shesh Nath Rai, Department of Bioinformatics and Biostatistics, University of Louisville School of Public Health and Information Sciences, Louisville, KY 40202, United States
Author contributions: Netz U, Eichenberger MR and Galandiuk S designed the research; Netz U, Carter JV, Eichenberger MR, Dryden GW and Galandiuk S collected the data; Netz U, Carter JV and Eichenberger MR performed the genetic labwork; Netz U, Carter JV, Eichenberger MR, Pan J, Rai SN and Galandiuk S analyzed and interpreted the data; all authors drafted the manuscript and approved the final version.
Institutional review board statement: The study was reviewed and approved by the University of Louisville Institutional Review Board.
Informed consent statement: All participants signed an informed consent statement as specified by the University of Louisville Institutional Review Board - Human Subjects Protection Program Office - No 97.0361.
Conflict-of-interest statement: All authors declare no conflict of interest.
Data sharing statement: The dataset is available from the corresponding author at [s0gala01@louisville.edu]. Consent for data sharing was not obtained but the presented data are anonymized and risk of identification is low.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Susan Galandiuk, MD, FACG, AGAF, Price Institute of Surgical Research, the Hiram C. Polk Jr. MD Department of Surgery, University of Louisville School of Medicine, 550 South Jackson Street, Louisville, KY 40202, United States. s0gala01@louisville.edu
Telephone: +1-502-8524568 Fax: +1-502-8528915
Received: February 7, 2017
Peer-review started: February 9, 2017
First decision: March 16, 2017
Revised: April 5, 2017
Accepted: May 4, 2017
Article in press: May 4, 2017
Published online: July 21, 2017
Processing time: 163 Days and 4.4 Hours
Abstract
AIM

To investigate genetic factors that might help define which Crohn’s disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy.

METHODS

This was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria).

RESULTS

121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.

CONCLUSION

The Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.

Keywords: Anti-tumor necrosis factor; Fas ligand; Antibody; Response; Crohn’s disease; Single nucleotide polymorphisms; Genotype; Tumor necrosis factor gene

Core tip: Predicting the subset of patients who do not respond to anti-tumor necrosis factor (TNF) treatment is important clinically and economically. Patients with Crohn’s disease who received anti-TNF therapy were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. 121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis and may help select patients likely to benefit from anti-TNF therapy.