title: Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
abstract: Psoriasis is an inflammatory skin disorder that is inherited as a multifactorial trait. Genetic analyses have repeatedly identified a primary disease susceptibility locus lying within the major histocompatibility complex (MHC), on chromosome 6p21. A small number of non-MHC susceptibility loci have also been identified. These regions tend to overlap with susceptibility intervals for Crohn's disease and atopic dermatitis, suggesting the possibility that genetic variants affecting inflammatory pathways may contribute to the pathogenesis of multiple disorders. Here, we report a genetic analysis of the interleukin 23 receptor gene (IL23R), which was recently identified as a susceptibility determinant for Crohn's disease. We initially examined the results of a whole-genome association scan, carried out on 318 cases and 288 controls. We observed a significant increase of a non-synonymous substitution (p.Arg381Gln) among controls (P = 0.00036). We validated this finding by extending our cohort to include a further 519 cases and 528 controls. In the overall sample, the frequency of the 381Gln allele was 3.6% in cases and 7% in controls, yielding a P value of 0.00014. Next, we examined genetic variation at the IL12RB1, IL23A and IL12B genes, respectively, encoding the second subunit of the IL23R receptor and the two subunits of its ligand. This analysis identified independent associations for IL12B SNPs rs10045431 (P value for the extended dataset = 0.0001) and rs3212227 (P = 0.036). Altogether, these findings indicate that genes participating in IL23 signalling play a significant role in the pathogenesis of chronic epithelial inflammation.
authors.affiliation: Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College, London, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
authors.forename: Paola
authors.initials: P
authors.lastname: Di Meglio
authors.forename: Joanna
authors.initials: J
authors.lastname: Szaub
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Prescott
authors.forename: Christina
authors.initials: C
authors.lastname: Dunster
authors.forename: Laura
authors.initials: L
authors.lastname: Baumber
authors.forename: Kirsten
authors.initials: K
authors.lastname: Timms
authors.forename: Alexander
authors.initials: A
authors.lastname: Gutin
authors.forename: Victor
authors.initials: V
authors.lastname: Abkevic
authors.forename: A David
authors.initials: AD
authors.lastname: Burden
authors.forename: Jerry
authors.initials: J
authors.lastname: Lanchbury
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Barker
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011565:Psoriasis / Q000235:genetics*; D018123:Receptors, Interleukin / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C500879:IL12B protein, human; C515500:IL23R protein, human; D053762:Interleukin-12 Subunit p40; D018123:Receptors, Interleukin