PXR and extensive ulcerative colitis

[Guest guest]

Dear All,

As I've mentioned several times in our newsletters, one of the most

interestng genes affecting ulcerative colitis susceptibility is the

pregnane X receptor (PXR). PXR is required for expression of MDR1,

another gene implicated in ulcerative colitis. PXR is down-regulated

in ulcerative colitis, and this may contribute to reduced expression

of MDR1 in ulcerative colitis. Down regulation of PXR and MDR1 may

cause susceptibility to various toxic compounds (xenobiotics),

including certain bile acids. PXR is activated by rifampin, and in

doing so may help detoxify bile acids, and suppress pruritus. Down-

regulation of PXR may also predispose to bowel inflammation, as

discussed in the article on 'Inflammation and Cholestasis' on pages 5-

8 of this issue of our newsletter:

http://www.pscpartners.org/NewsVol-2-4.pdf

The following recent paper confirms that PXR is an ulcerative colitis

susceptibility gene in the Spanish population, and is particularly

strongly associated with extensive colitis [i believe that this is

often called pancolitis, and is found more commonly in PSC].

Moreover, the paper shows an interaction between the PXR and MDR1

genes in patients with extensive UC:

_________________

Inflamm. Bowel Dis. [in Press] (2007)

Role of the PXR gene locus in inflammatory bowel diseases.

Alfonso Martínez, PhD 1, Ana Márquez, MSc 1, Mendoza, MD,

PhD 2, Taxonera, MD, PhD 2, Fernández-Arquero, PhD 1,

Díaz-Rubio, MD, PhD 2, Emilio G. de la Concha, MD, PhD 1,

Elena Urcelay, PhD 1 *

1Department of Immunology, Hospital Universitario San , Madrid

2Department of Gastroenterology, Hospital Universitario San ,

Madrid

email: Elena Urcelay (eurcelay.hcsc@...)

*Correspondence to Elena Urcelay, Immunology Department, Hospital

Universitario San , Lagos s/n, 28040 Madrid, Spain

Funded by:

Fundación Ramón Areces

Fundación Mutua Madrileña

Fondo Investigaciones Sanitarias; Grant Number: FIS CP04/00175

Fundación para la Investigación Biomédica-Hospital Clínico San

Keywords

pregnane X receptor gene • ulcerative colitis • Crohn's disease •

susceptibility

Abstract

Background: The pregnane X receptor gene (PXR/NR1I2) has been

recently associated with an increased risk for inflammatory bowel

disease (IBD), although a subsequent case-control study failed to

replicate the original association in an independent population. This

nuclear receptor regulates genes involved in the detoxification

process in the liver and intestine, like ABCB1/MDR1. PXR expression

was significantly reduced in the colon of patients with ulcerative

colitis (UC), but remained unaffected in Crohn's disease (CD)

patients. Considering previous results, we aimed at investigating the

impact of this locus on IBD predisposition in the Spanish population.

Methods: Three PXR polymorphisms, including the 1 more strongly

correlated with IBD risk in the initial study at -25385C/T

(rs3814055) and the 6 haplotypes conformed by them, were analyzed in

365 UC and 331 CD patients and compared with 550 ethnically matched

controls.

Results: The overall haplotypic distribution showed a significant

difference between UC and CD patients (P = 0.05; chi2 = 10.84). Among

UC patients a significant difference was seen between those with

extensive colitis and controls (P = 0.004; chi2 = 17.04), mainly due

to the presence of a risk haplotype

(rs3814055*T//rs6784598*C//rs2276707*C: P = 0.001; odds ratio [OR] =

1.66, 95% confidence interval [CI] 1.20-2.30). Patients with

extensive UC carrying the -25385T allele showed increased

susceptibility compared with left-sided colitis patients and with

healthy subjects. In patients with extensive UC a significantly

different distribution of genotypes of the MDR1 G/A change located in

intron 3 (rs3789243) was observed between carriers/noncarriers of

the -25385T risk allele (P = 0.005).

Conclusions: Our data seem to support the association of the PXR

locus with extensive UC and the interaction between PXR and MDR1

genes.

_________________

I've mentioned previously that the PXR gene has also been found to

affect the severity of PSC in the Scandinavian population.

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)