title: Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Gastrointestinal Unit, Western General Hospital, Edinburgh, Scotland, UK. gho@ed.ac.uk
authors.forename: Gwo-Tzer
authors.initials: GT
authors.lastname: Ho
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Nimmo
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
authors.forename: Janice
authors.initials: J
authors.lastname: Fennell
authors.forename: Hazel
authors.initials: H
authors.lastname: Drummond
authors.forename: Craig
authors.initials: C
authors.lastname: Mowat
authors.forename: Ian D
authors.initials: ID
authors.lastname: Arnott
authors.forename: Jack
authors.initials: J
authors.lastname: Satsangi
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics; D005091:Exons; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide