TY - JOUR
T1 - MDR1 Ala893 Polymorphism Is Associated with Inflammatory Bowel Disease
AU - Brant, Steven R.
AU - Panhuysen, Carolien I.M.
AU - Nicolae, Dan
AU - Reddy, Deepthi M.
AU - Bonen, Denise K.
AU - Karaliukas, Reda
AU - Zhang, Leilei
AU - Swanson, Eric
AU - Datta, Lisa W.
AU - Moran, Thomas
AU - Ravenhill, Geoffrey
AU - Duerr, Richard H.
AU - Achkar, Jean Paul
AU - Karban, Amir S.
AU - Cho, Judy H.
N1 - Funding Information:
This authors of this work are indebted to the patients with IBD and to their families, who gave of themselves to make this work possible. We thank Drs. Theodore M. Bayless, Stephen B. Hanauer, Mary Harris, Barbara Kirschner, and Themistocles Dassopoulos, who contributed data from families for this study; and Dr. Peter K. Gregersen, North Shore Long Island Jewish Research Institute, Manhasset, New York, who kindly provided DNA samples from Ashkenazi Jewish control individuals. Mr. Franklin Nouvet and Ms. Yuqiong Wu contributed to the genotyping. This work was supported by the National Institutes of Health (NIH) (National Institute of Diabetes and Digestive and Kidney Diseases) grants R01 DK58189 and U01 DK062431 (to S.R.B.); RO1 DK55731, U01 DK62429, and U01 DK062422 (to J.H.C.); and R01 DK060867 (to R.H.D.); by NIH–General Clinical Research Center grants RR00052 (to S.R.B.) and RR00055 (to J.H.C.); by the Crohn's and Colitis Foundation of America (to S.R.B., J.H.C., and R.H.D.); by the Meyerhoff IBD Center (to S.R.B., C.H.P, D.M.R., L.W.D., G.R., and A.S.K.); by the Stewart W. Bainum family (to S.R.B.); by the Reva and David Logan Foundation and Gastrointestinal Research Foundation (to D.K.B, R.K., E.S., T.M., and J.H.C.); by the Johns Hopkins University Provost Undergraduate Research Award (to D.M.R.); by the American College of Gastroenterology Clinical Research Award (to J.P.A.); by The Scaife Family Foundation (to R.H.D.); and by the Israeli Society of Gastroenterology (support to A.S.K.).
PY - 2003/12
Y1 - 2003/12
N2 - 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.
AB - 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.
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U2 - 10.1086/379927
DO - 10.1086/379927
M3 - Article
C2 - 14610718
AN - SCOPUS:9144224852
SN - 0002-9297
VL - 73
SP - 1282
EP - 1292
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -