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.

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

“…[7][8][9] Recently, we have reported psoriasis-associated diplotypes at IL12B, confirming and extending the previous work by Tsunemi et al, 10 and predisposing/protective diplotypes at IL23R using a multi-staged, case-control design, scanning 25 215 genecentric single nucleotide polymorphisms (SNPs). 11 These results have been verified in four independent studies [12][13][14][15] and have paralleled association studies in related diseases. One of the IL23R missense SNPs implicated in psoriasis, R381Q, has also been strongly associated with several autoinflammatory phenotypes: several studies have found R381Q-mediated predisposition to adult inflammatory bowel disease (IBD), especially Crohn's disease [16][17][18][19][20][21] and pediatric Crohn's disease in individuals of European descent, [22][23][24] two sizable studies reported association of multiple IL23R SNPs with ankylosing spondylitis (AS) 25,26 and a North American study demonstrated IL23R susceptibility for Graves' ophthalmopathy (GO).…”

Differential contribution of CDKAL1 variants to psoriasis, Crohn's disease and type II diabetes

“…2 Genome-wide linkage scans have unambiguously mapped a primary disease susceptibility locus (PSORS1) to the major histocompatibility complex (MHC), 3 where refinement studies and resequencing efforts point to HLA-C as the most likely PSORS1 candidate. 4,5 More recently, the advent of genome-wide association scans has allowed the identification of several non-MHC susceptibility genes, including IL12B, IL23R, RNF114, TNFAIP3, TNIP1, IL4/IL13 and LCE3B/3C [6][7][8][9][10][11] Of these, IL12B and IL23R harbour variants that also confer susceptibility to Crohn's disease (CD) 12 and ankylosing spondylitis. 13 Similarly, TNFAIP3 alleles have been associated with rheumatoid arthritis, 14 systemic lupus erythematosus 15 and type I diabetes.…”

Molecular genetics of the skin: the implications of understanding

“…The significance of all these loci is not yet understood, but the recent finding that polymorphisms in the interleukin 23 receptor and its ligand interleukin 12 influence susceptibility to psoriasis reflects evidence that biological therapy directed against these cytokines is effective. 14,15 In the case of atopic eczema, a predisposition locus at the epidermal differentiation complex is due at least in part to common null mutations in the gene encoding the epidermal barrier protein filaggrin. 16 Ten per cent of European subjects carry such mutations, which in the homozygous state cause ichthyosis vulgaris.…”