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Human Molecular Genetics Advance Access published online on January 5, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp005
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

TNFSF15 transcripts from risk haplotype for Crohn's disease are overexpressed in stimulated T cells

Yoichi Kakuta1,2, Nobuo Ueki1,2, Yoshitaka Kinouchi1,2,*, Kenichi Negoro1, Katsuya Endo1, Eiki Nomura1, Sho Takagi1, Seiichi Takahashi1 and Tooru Shimosegawa1

1 Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan

* Corresponding author: Yoshitaka Kinouchi, M.D. Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai, 980-8574, Japan Tel: +81-22-717-7171 Fax: +81-22-717-7177 E-mail: ykinouchi{at}int3.med.tohoku.ac.jp

Received October 10, 2008; Revised December 23, 2008; Accepted December 23, 2008

TNFSF15 is a susceptibility gene for Crohn's disease (CD). It remains to be elucidated how the associated SNPs in TNFSF15 affect the susceptibility to CD. Because there are no non-synonymous SNPs in TNFSF15, 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 firstly examined the allelic expression imbalance of TNFSF15 in peripheral blood mononuclear cells (PBMC). When PBMC stimulated by phytohemagglutinin (PHA) were examined, the allelic ratio of mRNA transcribed from the risk haplotype to 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 PBMC 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 -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.

2 Y.K., N.U. and Y.K contributed equally to this work.


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