title: Sequence variation, linkage disequilibrium and association with Crohn's disease on chromosome 5q31.
abstract: Chromosome 5q31 contains a cluster of genes involved in immune response, including a 250 kb risk haplotype associated with Crohn's disease (CD) susceptibility. Recently, two functional variants in SLC22A4 and SLC22A5 (L503F and G-207C), encoding the cation transporters OCTN1 and OCTN2, were proposed as causal variants for CD, but with conflicting genetic evidence regarding their contribution. We investigated this locus by resequencing the coding regions of 10 genes in 24 CD cases and deriving a linkage disequilibrium (LD) map of the 27 single nucleotide polymorphisms (SNPs) detected. Ten SNPs representative of the LD groups observed, were tested for CD association. L503F in SLC22A4 was the only nonsynonymous SNP significantly associated with CD (P=0.003), but was not associated with disease in the absence of other markers of the 250 kb risk haplotype. Two other SNPs, rs11242115 in IRF1 and rs17166050 in RAD50, lying outside the 250 kb risk haplotype, also showed CD association (P=0.019 and P=0.0080, respectively). The RAD50 gene contains a locus control region regulating expression of the Th2 cytokine genes at this locus. Other as yet undiscovered SNPs in this region may therefore modulate gene expression and contribute to the risk of CD, and perhaps of other inflammatory phenotypes.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Onnie
authors.forename: S A
authors.initials: SA
authors.lastname: Fisher
authors.forename: K
authors.initials: K
authors.lastname: King
authors.forename: M
authors.initials: M
authors.lastname: Mirza
authors.forename: R
authors.initials: R
authors.lastname: Roberts
authors.forename: A
authors.initials: A
authors.lastname: Forbes
authors.forename: J
authors.initials: J
authors.lastname: Sanderson
authors.forename: C M
authors.initials: CM
authors.lastname: Lewis
authors.forename: C G
authors.initials: CG
authors.lastname: Mathew
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D015331:Cohort Studies; D003424:Crohn Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D027701:Organic Cation Transport Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters
chemical_list: D027701:Organic Cation Transport Proteins; C109807:SLC22A4 protein, human; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D027981:Symporters