Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 14, 2018; 24(6): 657-670
Published online Feb 14, 2018. doi: 10.3748/wjg.v24.i6.657
Role of PTPN2/22 polymorphisms in pathophysiology of Crohn’s disease
Robert C Sharp, Shazia A Beg, Saleh A Naser
Robert C Sharp, Saleh A Naser, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
Shazia A Beg, University of Central College of Medicine, Health Center, Orlando, FL 32816, United States
Author contributions: Sharp RC is the primary author who performed all experiments, collected data and participated in writing the manuscript; Beg SA is the clinical coordinator in this study and has supervised recruitment of subjects, collection of clinical samples and transmitting of relevant data to the investigators. She played a vital role in analyzing the data and revising the manuscript; Naser SA is the leading investigator in the lab and has supervised all aspects of the study including writing and editing of the manuscript.
Supported by the Florida Legislative Grant and the Crohn’s Disease Grant Funded by the State of Florida (in part).
Institutional review board statement: The study was approved by the University of Central Florida Institutional Review Board #IRB00001138. Each subject completed and signed a written consent form before samples were collected. Each subject signed a written consent form for publication purposes.
Conflict-of-interest statement: The authors declare that they have no competing interests.
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: Saleh A Naser, PhD, Professor, Associate Director, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4110 Libra Drive, Orlando, FL 32816, United States. saleh.naser@ucf.edu
Telephone: +1-407-8230955 Fax: +1-407-8230955
Received: December 20, 2017
Peer-review started: December 21, 2017
First decision: December 27, 2017
Revised: January 3, 2018
Accepted: January 18, 2018
Article in press: January 18, 2018
Published online: February 14, 2018
Processing time: 47 Days and 9.9 Hours
Abstract
AIM

To establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22 (PTPN2/22) polymorphisms and mycobacterial infections in Crohn’s disease (CD).

METHODS

All 133 subjects’ blood samples were genotyped for nine single nucleotide polymorphisms (SNPs) in PTPN2/22 using TaqMan™ genotyping, while the effect of the SNPs on PTPN2/22 and IFN-γ gene expression was determined using RT-PCR. Detection of Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene was done by nPCR after DNA extraction from the isolated leukocytes of each subjects’ blood samples. T-cells isolated from the patient samples were tested for response to phytohematoagglutonin (PHA) mitogen or mycobacterial antigens by BrdU proliferation assays for T-cell activity.

RESULTS

Out of the nine SNPs examined, subjects with either heterozygous (TC)/minor (CC) alleles in PTPN2:rs478582 occurred in 83% of CD subjects compared to 61% healthy controls (P-values < 0.05; OR = 3.03). Subjects with either heterozygous (GA)/minor (AA) alleles in PTPN22:rs2476601 occurred in 16% of CD compared to 6% healthy controls (OR = 2.7). Gene expression in PTPN2/22 in CD subjects was significantly decreased by 2 folds compared to healthy controls (P-values < 0.05). IFN-γ expression levels were found to be significantly increased by approxiately 2 folds in subjects when either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 were found (P-values < 0.05). MAP DNA was detected in 61% of CD compared to only 8% of healthy controls (P-values < 0.05, OR = 17.52), where subjects with either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 had more MAPbacteremia presence than subjects without SNPs did. The average T-cell proliferation in CD treated with PHA or mycobacteria antigens was, respectively, 1.3 folds and 1.5 folds higher than healthy controls without any significant SNP.

CONCLUSION

The data suggests that SNPs in PTPN2/22 affect the negative regulation of the immune response in CD patients, thus leading to an increase in inflammation/apoptosis and susceptibility of mycobacteria.

Keywords: Crohn’s disease; PTPN2; PTPN22; PTPN2/22; Mycobacteria; Single nucleotide polymorphisms

Core tip: Knowledge of the pathophysiology of Crohn’s disease (CD) is vital in the development of new diagnosis techniques and treatments for the disease. Our study involves the investigation of single nucleotide polymorphisms (SNPs) in protein tyrosine phosphatase non-receptor type 2 and 22 (PTPN2/22) and their effects on susceptibility to mycobacteria species and the elevation of pro-inflammatory cytokines. Our data demonstrates that SNPs in PTPN2/22 lead to less negative regulation in T-cells and increase susceptibility to mycobacteria, thus increasing inflammation and apoptosis in intestinal tissues. Personalized treatment could be accomplished by genetic testing and antibiotic treatment for mycobacteria in CD patients.