Role of the PXR gene locus in inflammatory bowel diseases.
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; chi(2) = 10.84). Among UC patients a significant difference was seen between those with extensive colitis and controls (P = 0.004; chi(2) = 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.
Martínez
Alfonso
A
Department of Immunology, Hospital Universitario San Carlos, Madrid, Spain.
Márquez
Ana
A
Mendoza
JuanLuis
J
Taxonera
Carlos
C
Fernández-Arquero
Miguel
M
Díaz-Rubio
Manuel
M
de la Concha
Emilio G
EG
Urcelay
Elena
E
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics*; D013030:Spain; D044465:White People