Associations between ABCB1/MDR1 gene polymorphisms and Crohn's disease: A gene-wide study in a pediatric population

Abstract

Background: Functional studies support the involvement of the MDR1 gene in the pathways leading to Crolin's disease (CD). Two common single nucleotide polymorphfsms: (SNPs), C3435T and G2677T/A, thought to alter the function of the corresponding P-glycoprotein, have shown inconsistent associations with CD. We investigated whether DNA variants in the MPR1 gene were associated with susceptibility for CD and specific phenotypes in children. Methods: A case-control study was conducted at 3 gastroenterology clinics across Canada. Children with CD and population- or hospital-based controls were included. CD cases were classified using the Montreal Classification. Thirteon tag-SNPs and the C3435T variant in the MDR1 gene were jenotyped. Single-SNP allefic, genotype as well as gene-wide haplotype associations with CD and its phenotypes at diagnosis were assessed. Results: A total of 270 CD cases and 336 controls were studied. Most cases were male (56.3%), had disease location L3±LA (58.1%), and an inflammatory phenotype B1±p (88.5%). Allelic association analysis revealed that SNP rs17327442 was significantly associated with overall susceptibility to CD (odds ratio [OR] = 0.72, 95% confidence interval [CI] = 0.50-499, P = 0.04) but this association did not withstand corrections for multiple testing (q-value = 0.56). Genotype-phepotype amilysislindicated that 2 SNPs (rs10248420, P = 0.007, q-value = 0.07; rs2032583, P = 0.01, q-value = 0.07) were significantly associated with colonic disease. Five SNPs, rs1128503 (P = 0.02), rs1202184 (P = 0.008), rs1202186 (P = 0.02), rs2091766 (P = 0.03), and rs2235046 (P = 0.03) were nominally associated with noninflammatory CD. Specific haplotypes comprising of the tag-SNPs were significantly associated with either colonic or noninflammatory CD. Conclusions: Our comprehensive gene-wide analysis suggests that the MDR1 gene may be associated with clinical phenotypes of CD in children. Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.