title: Functional variants of OCTN cation transporter genes are associated with Crohn disease.
abstract: Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus of approximately 250 kb at 5q31 (IBD5) was previously associated with susceptibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of 11 single-nucleotide polymorphisms among individuals with Crohn disease, but the pathogenic lesion in the region has not yet been identified. We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G-->C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease. These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease.
authors.affiliation: Department of Medicine, University of Toronto, and Department of Immunology, Mount Sinai Hospital Samuel Lunenfeld Research Institute, Ontario, Canada.
authors.forename: Vanya D
authors.initials: VD
authors.lastname: Peltekova
authors.forename: Richard F
authors.initials: RF
authors.lastname: Wintle
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Rubin
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Qiqing
authors.initials: Q
authors.lastname: Huang
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Gu
authors.forename: Bill
authors.initials: B
authors.lastname: Newman
authors.forename: Mark
authors.initials: M
authors.lastname: Van Oene
authors.forename: David
authors.initials: D
authors.lastname: Cescon
authors.forename: Gordon
authors.initials: G
authors.lastname: Greenberg
authors.forename: Anne M
authors.initials: AM
authors.lastname: Griffiths
authors.forename: Peter H
authors.initials: PH
authors.lastname: St George-Hyslop
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002331:Carnitine / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D015331:Cohort Studies; D003424:Crohn Disease / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D053473:Nod2 Signaling Adaptor Protein; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D015347:RNA Probes; D017386:Sequence Homology, Amino Acid; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D015347:RNA Probes; C109807:SLC22A4 protein, human; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters; D002331:Carnitine