title: MDR1 Ala893 polymorphism is associated with inflammatory bowel disease.
abstract: Crohn disease (CD) and ulcerative colitis (UC) are overlapping chronic inflammatory bowel diseases (IBDs). Suggestive evidence for linkage at chromosome 7q has been reported for both CD and UC. Contained within this region is the gene for MDR1 (multidrug resistance), a membrane transport protein for which human polymorphisms have been reported in Ala893Ser/Thr and C3435T that alter pharmacokinetic profiles for a variety of drugs. Because mdr1 knockout mice spontaneously develop colitis, exonic regions were resequenced and tested for IBD association in a large, multicenter North American cohort. Two missense mutations, Asn21Asp and Ala893Ser/Thr, as well as the expression-associated polymorphism C3435T, described elsewhere, were genotyped in the entire cohort. Significant association of Ala893 with IBD was observed by both case-control analysis (P=.002) and the pedigree disequilibrium test (PDT [P=.00020-.00030]) but not for the Asn21Asp or C3435T polymorphisms. Significant association by PDT was observed within the subset with CD (P=.0014-.00090), with similar, nonsignificant trends in a smaller subset with UC. The Ala893Ser/Thr variant is triallelic, and the associated, common allele is Ala893, with undertransmission of the 893Ser (common) and the 893Thr (rare) variants. The Ala893 variant has decreased activity compared with the 893Ser variant; therefore, the association with human IBD is consistent with the murine model of mdr1 deficiency. Taken together, these data support the association of the common Ala893 polymorphism with IBD specifically and, more broadly, provides additional support for its contribution to interindividual pharmacogenetic variation.
authors: The 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
authors: Steven R
authors: SR
authors: Brant
authors: Carolien I M
authors: CI
authors: Panhuysen
authors: Dan
authors: D
authors: Nicolae
authors: Deepthi M
authors: DM
authors: Reddy
authors: Denise K
authors: DK
authors: Bonen
authors: Reda
authors: R
authors: Karaliukas
authors: Leilei
authors: L
authors: Zhang
authors: Eric
authors: E
authors: Swanson
authors: Lisa W
authors: LW
authors: Datta
authors: Thomas
authors: T
authors: Moran
authors: Geoffrey
authors: G
authors: Ravenhill
authors: Richard H
authors: RH
authors: Duerr
authors: Jean-Paul
authors: JP
authors: Achkar
authors: Amir S
authors: AS
authors: Karban
authors: Judy H
authors: JH
authors: Cho
mesh_terms: D000409:Alanine / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D017931:DNA Primers; D005787:Gene Frequency; D019450:Genes, MDR / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009656:North America; D010375:Pedigree; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D017931:DNA Primers; D000409:Alanine