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Human Molecular Genetics Advance Access originally published online on January 5, 2009
Human Molecular Genetics 2009 18(6):1089-1098; 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 Kakuta{dagger}, Nobuo Ueki{dagger}, Yoshitaka Kinouchi{dagger},*, Kenichi Negoro, Katsuya Endo, Eiki Nomura, Sho Takagi, Seiichi Takahashi and Tooru Shimosegawa

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

* To whom correspondence should be addressed. Tel: +81 227177171; Fax: +81 227177177; Email: ykinouchi{at}int3.med.tohoku.ac.jp

Received October 10, 2008; Accepted December 23, 2008

TNFSF15 is a susceptibility gene for Crohn's disease (CD). It remains to be elucidated how the associated single nucleotide polymorphisms (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 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.

{dagger} The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.


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