Abstract:
BACKGROUND AND AIMS:The MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The MDR1 exonic single nucleotide polymorphisms (SNPs) C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 170. METHODS:This was a case-control analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis [UC], 268 with Crohn's disease [CD], and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivariate genotypic-phenotypic analyses. RESULTS:The MDR1 3435 TT genotype (34.6% vs 26.5%; P = .04; odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.04-2.44) and T-allelic frequencies (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03-1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%; P = .003; OR, 2.64; 95% CI, 1.34-4.99; and T allele: 63.9% vs 52.8%; P = .009; OR, 1.70; 95% CI, 1.24-2.29), and this was also confirmed on multivariate analysis ( P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D', .8-.9; r 2 , .7-.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype: P = .03; OR, 1.44) and negative (C3435/2677T haplotype: P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC ( P = .017; OR, 8.88; 95% CI, 1.10-71.45). CONCLUSIONS:Allelic variations of the MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.
journal_name
Gastroenterologyjournal_title
Gastroenterologyauthors
Ho GT,Nimmo ER,Tenesa A,Fennell J,Drummond H,Mowat C,Arnott ID,Satsangi Jdoi
10.1053/j.gastro.2004.11.019keywords:
subject
Has Abstractpub_date
2005-02-01 00:00:00pages
288-96issue
2eissn
0016-5085issn
1528-0012pii
S001650850402030Xjournal_volume
128pub_type
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