https://scholars.lib.ntu.edu.tw/handle/123456789/565690
標題: | SLCO3A1, a novel Crohn's disease-associated gene, regulates NF-κB activity and associates with intestinal perforation | 作者: | SHU-CHEN WEI Tan, Y.-Y. Weng, M.-T. LIANG-CHUAN LAI Hsiao, J.-H. Chuang, E.Y. CHIA-TUNG SHUN Wu, D.-C. Kao, A.-W. Chuang, C.-S. YEN-HSUAN NI MING-JIUM SHIEH CHIEN-CHIH TUNG Chen, Y. Wang, C.-Y. Xavier, R.J. Podolsky, D.K. ERIC YAO-YU CHUANG |
公開日期: | 2014 | 出版社: | Public Library of Science | 卷: | 9 | 期: | 6 | 來源出版物: | PLoS ONE | 摘要: | Background & Aims: To date, only one gene (TNFSF15) has been identified and validated as a Crohn's disease (CD)-associated gene in non-Caucasian populations. This study was designed to identify novel CD-associated single nucleotide polymorphisms (SNPs)/genes and to validate candidate genes using a functional assay. Methods: SNPs from 16 CD patients and 16 age- and sex-matched control patients were analyzed using Illumina platform analysis. Subsequently, we expanded the study and followed 53 CD patients and 41 control patients by Sequenom MassArray analysis. Quantitative PCR and immunohistochemical staining were performed to assess mRNA and protein expression of the candidate gene on tissue isolated from CD patients. Genotype was correlated with CD phenotypes. Finally, the candidate gene was cloned and its effect on NF-κB activity assessed using a reporter luciferase assay. Results: SLCO3A1 (rs207959) reached statistical significance in the first-stage analysis ( P = 2.3E-02) and was further validated in the second-stage analysis (P = 1.0E-03). Genotype and phenotype analysis showed that the rs207959 (T) allele is a risk allele that alters SLCO3A1 mRNA expression and is associated with intestinal perforation in CD patients. Higher levels of mRNA and protein expression of SLCO3A1 were seen in CD patients compared with the control group. Overexpression of SLCO3A1 induced increased NF-κB activity and increased phosphorylation of P65, ERK, and JNK. Nicotine augmented the activation of NF-κB in the presence of SLCO3A1. Conclusions: SLCO3A1, a novel CD-associated gene, mediates inflammatory processes in intestinal epithelial cells through NF-κB transcription activation, resulting in a higher incidence of bowel perforation in CD patients. ? 2014 Wei et al. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84903289519&doi=10.1371%2fjournal.pone.0100515&partnerID=40&md5=4f67a4b1b819b1c51e72933d1324929f https://scholars.lib.ntu.edu.tw/handle/123456789/565690 |
ISSN: | 1932-6203 | DOI: | 10.1371/journal.pone.0100515 | SDG/關鍵字: | immunoglobulin enhancer binding protein; messenger RNA; mitogen activated protein kinase; nicotine; organic anion transporter D; stress activated protein kinase; synaptotagmin I; immunoglobulin enhancer binding protein; messenger RNA; mitogen activated protein kinase; nicotine; organic anion transporter; protein kinase B; SLCO3A1 protein, human; adolescent; adult; allele; article; controlled study; Crohn disease; disease association; DNA determination; female; gene expression; gene identification; gene overexpression; genotype phenotype correlation; human; human cell; human tissue; immunohistochemistry; inflammation; intestine epithelium cell; intestine perfusion; luciferase assay; major clinical study; male; molecular cloning; protein expression; protein phosphorylation; real time polymerase chain reaction; transcription initiation; aged; case control study; child; complication; Crohn disease; demography; drug effects; enzymology; genetic association; genetic predisposition; genetics; HEK293 cell line; intestine perforation; metabolism; middle aged; pathology; phosphorylation; single nucleotide polymorphism; young adult; Adolescent; Adult; Aged; Alleles; Case-Control Studies; Child; Crohn Disease; Demography; Female; Genetic Association Studies; Genetic Predisposition to Disease; HEK293 Cells; Humans; Intestinal Perforation; Male; Middle Aged; Mitogen-Activated Protein Kinases; NF-kappa B; Nicotine; Organic Anion Transporters; Phosphorylation; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-akt; RNA, Messenger; Young Adult |
顯示於: | 醫學系 |
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