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MDR1 Ala893 polymorphism is associated with inflammatory bowel disease
Steven R Brant1, Carolien I M Panhuysen, Dan Nicolae
1The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sbrant@jhmi.edu
American Journal of Human Genetics
|November 12, 2003
Summary
The common Ala893 polymorphism in the MDR1 gene is associated with inflammatory bowel diseases (IBD), including Crohn disease and ulcerative colitis. This finding supports the role of MDR1 in IBD pathogenesis and pharmacogenetics.
Area of Science:
- Genetics
- Gastroenterology
- Pharmacology
Background:
- Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) with overlapping features.
- Previous studies suggested a genetic linkage for IBD in chromosome 7q, which contains the multidrug resistance 1 (MDR1) gene.
- MDR1 (multidrug resistance) gene encodes a membrane transport protein, and its polymorphisms, such as Ala893Ser/Thr and C3435T, affect drug pharmacokinetics.
Purpose of the Study:
- To investigate the association between MDR1 gene polymorphisms and inflammatory bowel diseases (IBD) in a large North American cohort.
- To resequence exonic regions of the MDR1 gene and test for IBD association.
- To evaluate the functional impact of identified polymorphisms on IBD susceptibility.
Main Methods:
- Resequencing of MDR1 exonic regions and genotyping of polymorphisms (Asn21Asp, Ala893Ser/Thr, C3435T) in a multicenter North American cohort.
- Case-control analysis and pedigree disequilibrium test (PDT) were employed to assess IBD association.
- Functional assessment of the Ala893 variant's activity compared to the 893Ser variant.
Main Results:
- Significant association was found between the Ala893 polymorphism and IBD (P=.002 case-control, P=.00020-.00030 PDT).
- The association was particularly strong in Crohn disease patients (P=.0014-.00090 by PDT).
- The common allele is Ala893, with undertransmission of the 893Ser and 893Thr variants; Ala893 exhibits decreased activity compared to 893Ser.
Conclusions:
- The common Ala893 polymorphism in the MDR1 gene is significantly associated with inflammatory bowel diseases (IBD).
- This finding aligns with murine models of mdr1 deficiency and suggests a role for MDR1 in IBD pathogenesis.
- The study reinforces the contribution of MDR1 polymorphisms to interindividual pharmacogenetic variation.