title: Pilot study of Biomarkers for predicting effectiveness of ramosetron in diarrhea-predominant irritable bowel syndrome: expression of S100A10 and polymorphisms of TPH1.
abstract: BACKGROUND
  Serotonin type 3 receptor (5-HT3 R) antagonists are potentially useful therapeutic agents for diarrhea-predominant irritable bowel syndrome (IBS-D). To identify biomarkers predicting effectiveness of the 5-HT3 R 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.
  
  
  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
  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.
authors.affiliation: Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Shiotani
authors.forename: H
authors.initials: H
authors.lastname: Kusunoki
authors.forename: M
authors.initials: M
authors.lastname: Ishii
authors.forename: H
authors.initials: H
authors.lastname: Imamura
authors.forename: N
authors.initials: N
authors.lastname: Manabe
authors.forename: T
authors.initials: T
authors.lastname: Kamada
authors.forename: J
authors.initials: J
authors.lastname: Hata
authors.forename: J L
authors.initials: JL
authors.lastname: Merchant
authors.forename: K
authors.initials: K
authors.lastname: Haruma
mesh_terms: D000328:Adult; D017306:Annexin A2 / Q000378:metabolism*; D001562:Benzimidazoles / Q000008:administration & dosage*; D054316:Biomarkers, Pharmacological; D003967:Diarrhea / Q000150:complications / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D009418:S100 Proteins / Q000378:metabolism*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000008:administration & dosage*; D016896:Treatment Outcome; D014365:Tryptophan Hydroxylase / Q000235:genetics*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D001562:Benzimidazoles; D054316:Biomarkers, Pharmacological; D009418:S100 Proteins; D058831:Serotonin 5-HT3 Receptor Antagonists; D014365:Tryptophan Hydroxylase; D000099248:S100 Calcium Binding Protein A10; C071315:ramosetron; C497467:TPH1 protein, human
keywords: TPH1 rs211105; resistance; serotonin type 3 receptor antagonists