Functional analyses of TNFSF15 as a susceptibility gene for Crohn's disease.

2010 Fiscal Year Final Research Report

• Project/Area Number: 20590735
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tohoku University
• Principal Investigator: KINOUCHI Yoshitaka Tohoku University, 高等教育開発推進センター, 准教授 (20250780)
• Co-Investigator(Kenkyū-buntansha): KAKUTA Yoichi 東北大学, 医学系研究科, 非常勤講師 (50509205)
• Project Period (FY): 2008 – 2010
• Keywords: クローン病 / 感受性遺伝子 / TNFSF15 / allelic expression imbalance

Research Abstract

TNFSF15 is a susceptibility gene for Crohn's disease (CD). We speculated that one or more of the SNPs associated with CD may act as cis-regulatory SNPs. To reveal the effects of the SNPs on the transcriptional activity of TNFSF15, we first examined the allelic expression imbalance of TNFSF15 in peripheral blood mononuclear cells (PBMCs). When PBMCs stimulated by phytohemagglutinin (PHA) were examined, the allelic ratio of mRNA transcribed from the risk haplotype to the non-risk haplotype increased, compared with the ratio without stimulation. When peripheral blood T cells and Jurkat cells stimulated by phorbol 12-myristate 13-acetate + ionomycin were examined, an allelic expression imbalance similar to that observed in PBMCs stimulated by PHA was confirmed. The promoter assay in stimulated Jurkat cells showed that the luciferase activity of the promoter region (-979 to +35) of the risk haplotype was significantly higher than that of the non-risk haplotype, and deletion and mutagenesis analysis demonstrated that this difference resulted from the -358T/C SNP. The promoter activity of -358C (risk allele) was higher than that of -358T (non-risk allele) in stimulated T cells. This effect of -358T/C on the transcriptional activity in stimulated T cells may confer susceptibility to CD.

Research Products

• [Journal Article] TNFSF15 transcripts from risk haplotype for Crohn's disease are overexpressed in stimulated T cells. (2009)
  • Author(s): Kakuta Y, Ueki N, Kinouchi Y, Negoro K, Endo K, Nomura E, Takagi S, Takahashi S, Shimosegawa T.
  • Journal Title: Hum molecular Genetics 18(6) Pages: 1089-1098
  • Peer Reviewed
• [Journal Article] HLA-B is the best candidate of susceptibility genes in HLA for Japanese ulcerative colitis. (2009)
  • Author(s): Aizawa H, Kinouchi Y, Negoro K, Nomura E, Imai G, Takahashi S, Takagi S, Kakuta Y, Tosa M, Mochida A, Matsumura Y, Endo K, Shimosegawa T.
  • Journal Title: Tissue Antigens 73(6) Pages: 569-574
  • Peer Reviewed
• [Presentation] 日本人クローン病感受性遺伝子TNFSF15の機能解析 (2009)
  • Author(s): 木内喜孝
  • Organizer: 第95回日本消化器病学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2009-05-07
• [Presentation] The -360t/C Polymorphism in the Tnfsf15 Gene Influences the Transcriptional Activity in Activated T Lymphocytes. (2008)
  • Author(s): 木内喜孝
  • Organizer: 109th annual meeting of American Gastroenterological Association.
  • Place of Presentation: San Diego, USA.
  • Year and Date: 2008-05-19