Detailed genetic characterization of the interleukin-23 receptor in psoriasis.
ABSTRACT Using a multi-tiered, case-control association design, scanning 25 215 gene-centric SNPs, we previously identified two psoriasis susceptibility genes: IL12B and IL23R. These results have recently been confirmed. To better characterize the IL23R psoriasis-association, we used a fine mapping strategy to identify 59 additional IL23R-linked SNPs, which were genotyped in our three independent, white North American sample sets (>2800 individuals in toto). A sliding window of haplotype association demonstrates colocalization of psoriasis susceptibility effects within the boundaries of IL23R across all sample sets, thereby decreasing the likelihood that neighboring genes, particularly IL12RB2, are driving the association at this region. Additional haplotype work identified two 5-SNP haplotypes with strong protective effects, consistent across our three sample sets (OR(common)=0.67; P(comb)=4.32E-07). Importantly, heterogeneity of effect was extremely low between sample sets for these haplotypes (P(Het)=0.961). Together, these protective haplotypes attain a frequency of 16% in controls, declining to 11% in cases. The characterization of association patterns within IL23R to specific predisposing/protective variants will play an important role in the elucidation of psoriasis etiology and other related phenotypes. Further, this work is essential to lay the foundation for the role of IL23R genetics in response to pharmaceutical therapy and dosage.
Article: Biology of interleukin-22.[show abstract] [hide abstract]
ABSTRACT: Interleukin (IL)-22 is a member of the IL-10 family of cytokines and represents an important effector molecule of activated Th22, Th1, and Th17 cells, as well as Tc-cell subsets, gammadelta T cells, natural killer (NK), and NKT cells. IL-22 mediates its effects via a heterodimeric transmembrane receptor complex consisting of IL-22R1 and IL-10R2 and subsequent Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathways including Jak1, Tyk2, and STAT3. Whereas in some aspects, IL-22 acts synergistically with tumor necrosis factor-alpha, IL-1beta, or IL-17, most functions of IL-22 are unique. Importantly, IL-22 does not serve the communication between immune cells. It mainly acts on epithelial cells and hepatocytes, where it favors the antimicrobial defense, regeneration, and protection against damage and induces acute phase reactants and some chemokines. This chapter illuminates in detail the properties of IL-22 with respect to its gene, protein structure, cellular sources, receptors, target cells, biological effects, and, finally, its role in chronic inflammatory diseases, tumors, and infection.Seminars in Immunopathology 03/2010; 32(1):17-31. · 6.27 Impact Factor