title: SLCO3A1, A novel crohn's disease-associated gene, regulates nf-κB activity and associates with intestinal perforation.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Wei
authors.affiliation: Graduate Institute of Medical Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Yan-Yin
authors.initials: YY
authors.lastname: Tan
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Departments of Internal Medicine, Far Eastern Memorial Hospital, New Taipei, Taiwan.
authors.forename: Meng-Tzu
authors.initials: MT
authors.lastname: Weng
authors.affiliation: Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan; Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Liang-Chuan
authors.initials: LC
authors.lastname: Lai
authors.affiliation: Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Jen-Hao
authors.initials: JH
authors.lastname: Hsiao
authors.affiliation: Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Chuang
authors.affiliation: Department of Pathology and Forensic Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.affiliation: Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Deng-Cheng
authors.initials: DC
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ai-Wen
authors.initials: AW
authors.lastname: Kao
authors.affiliation: Department of Internal Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chiao-Shung
authors.initials: CS
authors.lastname: Chuang
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yen-Hsuan
authors.initials: YH
authors.lastname: Ni
authors.affiliation: Graduate Institute of Medical Engineering, National Taiwan University, Taipei, Taiwan; Deparment of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ming-Jium
authors.initials: MJ
authors.lastname: Shieh
authors.affiliation: Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Tung
authors.affiliation: Pediatric Surgery, Far Eastern Memorial Hospital, New Taipei, Taiwan.
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: UT Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Podolsky
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Medical Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Jau-Min
authors.initials: JM
authors.lastname: Wong
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D003424:Crohn Disease / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D003710:Demography; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007416:Intestinal Perforation / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D016328:NF-kappa B; D027361:Organic Anion Transporters; D012333:RNA, Messenger; C479544:SLCO3A1 protein, human; D009538:Nicotine; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases