Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome bowel habit subtypes

Am J Gastroenterol. 2013 Nov;108(11):1766-74. doi: 10.1038/ajg.2013.304. Epub 2013 Sep 24.


Objectives: Alterations in 5-hydroxytryptamine (5-HT) signaling have been implicated as a factor contributing to the altered bowel habit of irritable bowel syndrome (IBS) patients. Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme in enterochromaffin cell 5-HT biosynthesis. We hypothesized that genetic variants affecting TPH1 gene expression might alter intestinal 5-HT bioavailability and subsequently the propensity for distinct bowel habit subtypes in IBS. In this study, we assessed the only common TPH1 proximal promoter variant (-347C/A; rs7130929) and its association with bowel habit predominance in IBS.

Methods: Electrophoretic mobility shift assays were performed to assess whether the -347C/A-allele variant affects the DNA binding of nuclear factors. Genotype distribution was determined for 422 IBS patients subtyped using the Rome III criteria and for 495 healthy controls recruited from two university medical centers. Association with bowel habit was tested using a multinomial logistic regression model controlling for race, anxiety, depression, and study site.

Results: Early growth response factor 1 (EGR-1) bound with higher affinity to a site comprising the minor A-allele of single-nucleotide polymorphism (SNP) -347C/A. TPH1 genotype frequencies did not differ between IBS patients and controls overall. The CC genotype was more prevalent in the IBS-D subtype (47%) than in the IBS-C (25%) and IBS-M (37%) subtypes (P=0.039) after adjusting for race and other covariates. Colonic biopsies from a small cohort of IBS patients from one center were tested for higher TPH1 mRNA expression in samples with CC compared with the CA genotype, but the results did not reach statistical significance.

Conclusions: The TPH1 promoter SNP -347C/A differentially binds EGR-1 and correlates with IBS bowel habit subtypes and possibly colonic TPH1 expression consistent with its role in modulating intestinal 5-HT signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Alleles
  • Colon / physiopathology
  • Constipation / complications
  • Constipation / genetics*
  • Constipation / physiopathology
  • Defecation / genetics*
  • Diarrhea / complications
  • Diarrhea / genetics*
  • Diarrhea / physiopathology
  • Early Growth Response Protein 1 / genetics
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Intestinal Mucosa / physiopathology
  • Irritable Bowel Syndrome / complications
  • Irritable Bowel Syndrome / genetics*
  • Irritable Bowel Syndrome / physiopathology
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Tryptophan Hydroxylase / genetics*


  • EGR1 protein, human
  • Early Growth Response Protein 1
  • TPH1 protein, human
  • Tryptophan Hydroxylase