Pilot study of Biomarkers for predicting effectiveness of ramosetron in diarrhea-predominant irritable bowel syndrome: Expression of S100A10 and polymorphisms of TPH1

A. Shiotani, H. Kusunoki, M. Ishii, H. Imamura, N. Manabe, T. Kamada, J. Hata, J. L. Merchant, K. Haruma

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Background: Serotonin type 3 receptor (5-HT3R) antagonists are potentially useful therapeutic agents for diarrhea-predominant irritable bowel syndrome (IBS-D). To identify biomarkers predicting effectiveness of the 5-HT3R antagonist (ramosetron) in IBS-D. Methods: Irritable bowel syndrome-D Japanese subjects received 2.5 or 5 μg of ramosetron once daily for 4 weeks. Colonic mucosal S100A and tryptophan hydroxylase (TPH) mRNA expression levels were measured before treatment. Genomic DNA was extracted from blood and polymorphisms of TPH1 and TPH2 were analyzed. Key Results: Forty-two patients (27 men and 15 women, mean age 42 years) with IBS-D were included for analysis. Improvement of IBS symptoms was seen in 26 (61.9%). Baseline S100A10 (p = 0.02) and TPH1 (p = 0.02) expression were significantly higher in the ramosetron responders than in the non-responders. The frequencies of the TPH1 rs4537731G allele in linkage disequilibrium with the TPH1 rs7130929 T allele (11.5% vs 50%, p = 0.003; OR: 12; 95% CI: 2.1-69) along with TPH1 rs211105 C allele (3.8% vs 43.8%, p = 0.0003; OR: 19; 95% CI: 2.1-181) were significantly lower in the responders than in the non-responders. The mean scores of diarrhea at baseline were significantly higher (5.2 vs 3.7, p = 0.005) in patients with TPH1 rs211105 T/T than those with the G allele. Conclusions & Inferences: TPH1 gene polymorphisms and S100A10 expression, which correlate with 5-HT signaling were associated with ramosetron effectiveness in IBS-D, and may possibly lead to prospective identification of the resistance to treatment.

Original languageEnglish (US)
Pages (from-to)82-91
Number of pages10
JournalNeurogastroenterology and Motility
Volume27
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Keywords

  • Resistance
  • Serotonin type 3 receptor antagonists
  • TPH1 rs211105

ASJC Scopus subject areas

  • Physiology
  • Endocrine and Autonomic Systems
  • Gastroenterology

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