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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Gastroenterol
2013 ; 108
(11
): 1766-74
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Identification of a functional TPH1 polymorphism associated with irritable bowel
syndrome bowel habit subtypes
#MMPMID24060757
Grasberger H
; Chang L
; Shih W
; Presson AP
; Sayuk GS
; Newberry RD
; Karagiannides I
; Pothoulakis C
; Mayer E
; Merchant JL
Am J Gastroenterol
2013[Nov]; 108
(11
): 1766-74
PMID24060757
show ga
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.