title: 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 Crohn's disease (CD). Two common single nucleotide polymorphisms (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 MDR1 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. Thirteen tag-SNPs and the C3435T variant in the MDR1 gene were genotyped. Single-SNP allelic, 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+/-L4 (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] = 0.50-0.99, P = 0.04) but this association did not withstand corrections for multiple testing (q-value = 0.56). Genotype-phenotype analysis indicated 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.
authors.affiliation: Research Centre, Ste-Justine Hospital, Montreal, Quebec, Canada.
authors.forename: Alfreda
authors.initials: A
authors.lastname: Krupoves
authors.forename: Ernest G
authors.initials: EG
authors.lastname: Seidman
authors.forename: David
authors.initials: D
authors.lastname: Mack
authors.forename: David
authors.initials: D
authors.lastname: Israel
authors.forename: Kenneth
authors.initials: K
authors.lastname: Morgan
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambrette
authors.forename: Irina
authors.initials: I
authors.lastname: Costea
authors.forename: Colette
authors.initials: C
authors.lastname: Deslandres
authors.forename: Guy
authors.initials: G
authors.lastname: Grimard
authors.forename: Liliane
authors.initials: L
authors.lastname: Law
authors.forename: Emile
authors.initials: E
authors.lastname: Levy
authors.forename: Devendra K
authors.initials: DK
authors.lastname: Amre
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D002648:Child; D003424:Crohn Disease / Q000453:epidemiology* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D023281:Genomics; D006239:Haplotypes; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1