The pregnane X receptor locus is associated with susceptibility to inflammatory bowel disease

被引:148
作者
Dring, MM
Goulding, CA
Trimble, VI
Keegan, D
Ryan, AW
Brophy, KM
Smyth, CM
Keeling, PWN
O'Donoghue, D
O'Sullivan, M
O'Morain, C
Mahmud, N
Wikström, AC
Kelleher, D
McManus, R [1 ]
机构
[1] St James Hosp, Trinity Ctr Hlth Sci, Dept Clin Med, Dublin 8, Ireland
[2] St James Hosp, Inst Mol Med, Dublin Mol Med Ctr, Dublin 8, Ireland
[3] Trinity Coll Dublin, St James Hosp, Dublin, Ireland
[4] St Vincents Hosp, Dept Gastroenterol, Dublin 4, Ireland
[5] Adelaide & Meath Incorporating Natl Childrens Hos, Trinity Ctr Hlth Sci, Dept Clin Med, Dublin, Ireland
[6] Karolinska Inst, Dept Med Nutr, Huddinge, Sweden
关键词
D O I
10.1053/j.gastro.2005.12.008
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: The pregnane X receptor (PXR) regulates an array of genes involved in the response to xenobiotics. Evidence from several studies suggests that xenobiotic metabolism may play a role in inflammatory bowel disease (IBD) and that low levels of PXR may be associated with disease expression. The aim of this study was to investigate the association of functional polymorphisms of the PXR encoding gene (NR1/2) with disease in IBD populations. Methods: This was a case-control study examining 8 NR1/2 single nucleotide polymorphisms (SNIPS) previously associated with altered activity of PXR-regulated genes in an Irish cohort including 422 patients with 1131) and 350 ethnically matched controls. Results: We showed significant associations of NR1/2 with 11313, Crohn's disease (CID), and ulcerative colitis (UC) groups compared with a control population for SNIPS -23585 (IBD: P =.000008; odds ratio [OR], :1.62; 95% confidence interval [CI], 1.31-2.00) and -24381 (IBD: P=.0002; OR, 1.50; 95% Cl, 1.21-1.84). SNPs 7635 (P=.0008) and 8055 (P =.007) were found to be associated with 1131) and CD but not UC. Risk of IBD is strongly correlated to genotype at these sites, especially for the -25385CC genotype (P =.00001; OR, 2.92; 95% Cl, 1.87-4.66). We also show specific correlations of IBD phenotype with genotypes and haplotypes in the patient group. Conclusions: These results show that genetic variation in the PXR encoding gene, which has been associated with altered activity of PXR, is strongly associated with susceptibility to IBD, CD, and UC.
引用
收藏
页码:341 / 348
页数:8
相关论文
共 30 条
[11]   Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease [J].
Hugot, JP ;
Chamaillard, M ;
Zouali, H ;
Lesage, S ;
Cézard, JP ;
Belaiche, J ;
Almer, S ;
Tysk, C ;
O'Morain, CA ;
Gassull, M ;
Binder, V ;
Finkel, Y ;
Cortot, A ;
Modigliani, R ;
Laurent-Puig, P ;
Gower-Rousseau, C ;
Macry, J ;
Colombel, JF ;
Sahbatou, M ;
Thomas, G .
NATURE, 2001, 411 (6837) :599-603
[12]  
Hustert E, 2001, DRUG METAB DISPOS, V29, P1454
[13]   The nuclear pregnane X receptor: A key regulator of xenobiotic metabolism [J].
Kliewer, SA ;
Goodwin, B ;
Willson, TM .
ENDOCRINE REVIEWS, 2002, 23 (05) :687-702
[14]   5′ Diversity of human hepatic PXR (NR1I2) transcripts and identification of the major transcription initiation site [J].
Kurose, K ;
Koyano, S ;
Ikeda, S ;
Tohkin, M ;
Hasegawa, R ;
Sawada, JI .
MOLECULAR AND CELLULAR BIOCHEMISTRY, 2005, 273 (1-2) :79-85
[15]   Loss of detoxification in inflammatory bowel disease: Dysregulation of pregnane X receptor target genes [J].
Langmann, T ;
Moehle, C ;
Mauerer, R ;
Scharl, M ;
Liebisch, G ;
Zahn, A ;
Stremmel, W ;
Schmitz, G .
GASTROENTEROLOGY, 2004, 127 (01) :26-40
[16]   Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and navel susceptibility candidate genes [J].
Lawrance, IC ;
Fiocchi, C ;
Chakravarti, S .
HUMAN MOLECULAR GENETICS, 2001, 10 (05) :445-456
[17]   The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions [J].
Lehmann, JM ;
McKee, DD ;
Watson, MA ;
Willson, TM ;
Moore, JT ;
Kliewer, SA .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 102 (05) :1016-1023
[18]   High-throughput SNP genotyping by allele-specific PCR with universal energy-transfer-labeled primers [J].
Myakishev, MV ;
Khripin, Y ;
Hu, S ;
Hamer, DH .
GENOME RESEARCH, 2001, 11 (01) :163-169
[19]   Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB [J].
Ogura, Y ;
Inohara, N ;
Benito, A ;
Chen, FF ;
Yamaoka, S ;
Núñez, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (07) :4812-4818
[20]   FAMILIAL OCCURRENCE OF INFLAMMATORY BOWEL-DISEASE [J].
ORHOLM, M ;
MUNKHOLM, P ;
LANGHOLZ, E ;
NIELSEN, OH ;
SORENSEN, TIA ;
BINDER, V .
NEW ENGLAND JOURNAL OF MEDICINE, 1991, 324 (02) :84-88