Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis

doi:10.1053/j.gastro.2004.11.019

Gastroenterology

Volume 128, Issue 2, February 2005, Pages 288-296

https://doi.org/10.1053/j.gastro.2004.11.019 Get rights and content

Background & 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; r², .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.

Section snippets

Patients

This study was approved by the Lothian Research and Ethics Committee, and written consent was obtained from all patients. A total of 335 patients with UC and 268 with CD were recruited from the Lothian region (Scotland). The diagnosis of IBD was determined by standard clinical, radiologic, endoscopic, and histologic criteria.

Table 1, Table 2 summarize the clinical characteristics of patients studied. The median ages at diagnosis of UC and CD were 35.0 years (interquartile range, 25.3–50.3

Effect of MDR1 C3435T and G2677T polymorphism on overall disease susceptibility

Both the T allele and TT genotype of the MDR1 3435 SNP were significantly increased in patients with UC (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03–1.58) compared with healthy controls (34.6% vs 26.5%; P = .04; OR, 1.60; 95% CI, 1.04–2.44) (Table 3). No significant differences in allele or genotype frequencies were seen in patients with CD (53.0% vs 52.8% [P = .43] and 26.9% vs 26.5% [P = .81], respectively) when compared with controls. A trend toward higher T-allele and genotype

Discussion

This study firstly provides replicated confirmation for the association of the MDR1 C3435T SNP with UC. In addition, we have made novel observations with respect to genotype-phenotype correlations, notably the strong association of the C3435T SNP with extensive UC. Finally, the haplotypic analyses involving C3435T and G2677T SNPs provide further new insights into the complexities of the contribution of the MDR1 gene; both protective and susceptible haplotypes were identified.

Indeed, in view of

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¹: G.-T.H. is supported by the Chief Scientist Office, Scottish Executive, United Kingdom

²: E.R.N. and H.D. are supported by the Wellcome Trust, United Kingdom.

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Clinical-alimentary tractAllelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis

Section snippets

Patients

Effect of MDR1 C3435T and G2677T polymorphism on overall disease susceptibility

Discussion

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Hum Immunol

Gastroenterology

Gastroenterology

Gastroenterology

Am J Hum Genet

Gastroenterology

Gastroenterology

Hum Immunol

Gastroenterology

J Pharm Sci

Inflammatory bowel disease

N Engl J Med

Multidrug resistance 1 gene (P-glycoprotein 170)an important determinant in gastrointestinal disease?

Gut

Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues

Proc Natl Acad Sci U S A

Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites

Proc Natl Acad Sci U S A

Expression of a multidrug-resistance gene in human tumors and tissues

Proc Natl Acad Sci U S A

A novel model of inflammatory bowel diseasemice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis

J Immunol

Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12

Nat Genet

Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs

Hum Mol Genet

Functional polymorphisms of the human multidrug-resistance genemultiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo

Proc Natl Acad Sci U S A

Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects

Clin Pharmacol Ther

Identification of functionally variant MDR1 alleles among European Americans and African Americans

Clin Pharmacol Ther

Clinical-alimentary tract
Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis