Role of PTPN2/22 polymorphisms in pathophysiology of Crohn's disease  

作　　者：Robert C Sharp Shazia A Beg Saleh A Naser 

机构地区：[1]Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida [2]University of Central College of Medicine, Health Center,Orlando

出　　处：《World Journal of Gastroenterology》2018年第6期657-670,共14页世界胃肠病学杂志（英文版）

基　　金：Supported by the Florida Legislative Grant and the Crohn’s Disease Grant Funded by the State of Florida(in part)

摘　　要：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 Brd U 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. T h e 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 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 Brd U 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. T h e 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

关 键 词：Crohn’s DISEASE PTPN2 PTPN22 PTPN2/22 MYCOBACTERIA single NUCLEOTIDE POLYMORPHISMS 

分 类 号：R574.62[医药卫生—消化系统]