Background&Aims: The MDR1 gene encodes P-glycoprotein 170, an efflux transpo rter that is highly expressed in intestinal epithelial cells. The MDR1 exonic si ngle nucleotide polymorphisms(SNPs) C3435T and G2677T h...Background&Aims: The MDR1 gene encodes P-glycoprotein 170, an efflux transpo rter that is highly expressed in intestinal epithelial cells. The MDR1 exonic si ngle nucleotide polymorphisms(SNPs) C3435T and G2677T have been shown to correla te with activity/expression of P-glycoprotein 170.Methods: This was a case-con trol analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scot tish white cohort (335 with ulcerative colitis [UC], 268 with Crohn’s disease[C D], and 370 healthy controls). We conducted 2-locus haplotype and detailed univ ariate and multivariate genotypicphenotypic analyses. Results: The MDR1 3435 TT genotype(34.6%vs 26.5%; P =. 04; odds ratio [OR], 1.60; 95%confidence interva l [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 compare d with controls.No associationwas seen with CD. The association was strongest wi th 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; r2,. 7-.8). Two-locus haplotypes showed both positiv e (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/G26 77 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 wel l as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the nee d for further detailed haplotypic studies.展开更多
文摘Background&Aims: The MDR1 gene encodes P-glycoprotein 170, an efflux transpo rter that is highly expressed in intestinal epithelial cells. The MDR1 exonic si ngle nucleotide polymorphisms(SNPs) C3435T and G2677T have been shown to correla te with activity/expression of P-glycoprotein 170.Methods: This was a case-con trol analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scot tish white cohort (335 with ulcerative colitis [UC], 268 with Crohn’s disease[C D], and 370 healthy controls). We conducted 2-locus haplotype and detailed univ ariate and multivariate genotypicphenotypic analyses. Results: The MDR1 3435 TT genotype(34.6%vs 26.5%; P =. 04; odds ratio [OR], 1.60; 95%confidence interva l [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 compare d with controls.No associationwas seen with CD. The association was strongest wi th 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; r2,. 7-.8). Two-locus haplotypes showed both positiv e (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/G26 77 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 wel l as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the nee d for further detailed haplotypic studies.
