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.

Pregnane-X-receptor mediates the anti-inflammatory activities of rifaximin on detoxification pathways in intestinal epithelial cells

“…Further, MDR1a polymorphisms increase the susceptibility to IBD [23,24]. These data highlight the fact that the intestinal detoxification system serves a dual role during inflammation, both sending out inflammatory signals as well as protecting the intestinal epithelium.…”

“…The ABCB1 (MDR1) and additional ABC transporters with a high expression in the gut such as ABCC1-3 (MRP1-3) are critically involved in the maintenance of the intestinal barrier by excluding drugs, nutrients, or bacterial compounds back into the gut lumen [22,[30][31][32]. Furthermore, the association of MDR1 gene polymorphisms with susceptibility for IBD [23,24] implies that genetic [16,19].…”

Inflammatory bowel disease: Genetic and epidemiologic considerations

“…Present approaches have not been able to discern whether these other genes or the class Ⅱ genes are the true risk genes in the HLA locus. [79][80][81][82] , multiple polymorphisms in the MDR1/ABCB1 gene on chromosome 7q [83][84][85][86][87][88][89][90][91][92] , and polymorphisms in the DLG5 gene on chromosome 10q [70,[93][94][95][96][97][98][99][100][101][102] . (See section C.4.1.)…”

NOD2 gene mutations in ulcerative colitis: useless or misunderstood?

“…NOD2, the first gene linked with increased susceptibility to CD, has later been shown to be associated with ileal disease, early age of onset, stricturing, and/or penetrating phenotype and increased need for surgery [5,9,10,[38][39][40][41][42][43][44][45][46][47][48][49]. Among the UC susceptibility genes, HLA DRB1*0103 and the multidrug resistance gene 1 (MDR1/ABCB1) were also identified as being associated with extensive and severe disease [17,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37].…”

“…Among the UC susceptibility genes, HLA DRB1*0103 and the multidrug resistance gene 1 (MDR1/ABCB1) also contribute to clinical phenotype and natural history, being associated with extensive and severe disease [17,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. In CD, NOD2 gene mutations have repeatedly been shown to be associated with ileal disease, early age of onset, stricturing, and/or penetrating phenotype and increased need for surgery [5,9,10,[38][39][40][41][42][43][44][45][46][47][48][49].…”