ORIGINAL ARTICLE Association analysis of IL20RA and IL20RB genes in psoriasis K Kingo 1,2 , R Mo ¨ ssner 3 , R Ra ¨tsep 2,4 , K Raud 2,4 , U Kru ¨ ger 3 , H Silm 1 , E Vasar 2,4 , K Reich 5 and S Ko ˜ks 2,4,6 1 Department of Dermatology and Venerology, University of Tartu, Tartu, Estonia; 2 Centre of Molecular and Clinical Medicine, University of Tartu, Tartu, Estonia; 3 Department of Dermatology and Venerology, Georg-August-University Go ¨ttingen, Germany; 4 Department of Physiology, University of Tartu, Tartu, Estonia; 5 Dermatologikum, Hamburg, Germany and 6 Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, Tartu, Estonia The interleukin-20-receptor I complex (IL-20-RI) is composed of two chains, IL20RA and IL20RB. Its ligands are the three members of the IL19 subfamily of cytokines, IL-19, IL-20 and IL-24. These cytokines are important in the manifestation of psoriatic lesions and, recently, an association of polymorphisms of IL20 with psoriasis has been described. In the present study we tested the hypotheses that genetic variations of the IL-20-RI influence susceptibility to psoriasis and investigated single nucleotide polymorphisms (SNPs) in the IL20RA and IL20RB genes in psoriasis patients (n ¼ 254) and healthy controls (n ¼ 224). We found no association of any of the investigated SNPs with the disease. Analysis of pairwise linkage disequilibrium (LD) across studied markers revealed a strong level of LD between SNPs within the IL20RA gene and SNPs within the IL20RB gene, and, for both genes six common haplotypes were identified with an estimated frequency X1%. Haplotype analyses suggested that the IL20RA haplotype CCG (rs1184860, rs1167846, rs1167849) is significantly associated with psoriasis (OR 3.14, 95% CI 1.61–6.14), whereas the TTG haplotype had a protective effect (OR 0.20, 95% CI 0.07–0.55). The risk haplotype defining SNPs 1167846 and 1184860 were found to modify paired box 5 and homeobox A9 sites, respectively, two transcription factors related to the differentiation of immune cells. Further studies are needed to confirm the genetic association and to investigate the functional relevance of IL20RA haplotypes in psoriasis. Genes and Immunity (2008) 9, 445–451; doi:10.1038/gene.2008.36; published online 15 May 2008 Keywords: psoriasis; interleukin-20 receptor; single nucleotide polymorphisms; haplotypes Introduction Interleukin (IL)-19, IL-20 and IL-24 have recently been identified as a group of IL-10-related cytokines, which are now referred to as the IL-19 subfamily of cytokines based on their analogous genomic localization, protein structure, cellular sources, receptors and target cells. 1–3 It has been verified that IL-19 subfamily cytokines are regulators of epidermal keratinocyte biology and are important in the immunopathology of psoriasis. 4–6 The expression levels of IL-19, IL-20 and IL-24 in lesional skin of psoriasis patients are increased compared to healthy skin. 2,7–11 Two independent studies have demonstrated that overexpression of IL-20 in transgenic mice induces a skin phenotype similar to psoriasis. 2,5 Both in vitro and in vivo, IL-20 promotes hyperprolifera- tion and abnormal differentiation of keratinocytes that are characteristic features of psoriasis. 2,12,13 IL-19 has been shown to induce expression of keratinocyte growth factor, which acts as a potent mitogen for human keratinocytes. 14 and is considered to contribute to the epidermal hyperplasia in psoriasis. We have previously studied the possible impact of single nucleotide polymorphisms (SNPs) in the genes encoding the IL-19 subfamily of cytokines on the risk to develop psoriasis. Evidence was obtained that the IL19 gene cluster represents a susceptibility region shared by plaque-type psoriasis and palmoplantar pustulosis (PPP), offering a possible explanation at the genetic level for the frequent co-existence of PPP and plaque-type psoriasis. 15–18 The biological activities of the IL-19 subfamily cyto- kines are mediated through binding to two distinct cell-surface receptors, the IL-20 receptor type I (IL-20-RI) and type II (IL-20-RII). Both receptors are heterodimers and share the IL-20RB protein as common subunit. IL-20RB associates with IL-20RA to form IL-20RI that binds IL-19, IL20 and IL-24, and IL-20RB associates with IL-22RA1 to form IL-20-RII that binds IL-20 and IL-24. 2,13,19–21 After binding of the different ligands to the receptor complexes, signals are predominantly trans- ducted via Janus kinase-signal transducer and activation of transcription pathways. 22 IL-20-RI is mainly expressed in the skin, lung and reproductive organs as well as in various glands. The expression of IL-20-RII seems to be more restricted with high levels detectable only in the skin. 2,13,19–21 There are conflicting findings with regard to the expression of IL-20R subunits in skin lesions of psoriasis. Received 1 April 2008; accepted 2 April 2008; published online 15 May 2008 Correspondence: Dr S Ko ˜ks, Department of Physiology, University of Tartu, 19 Ravila Street, Tartu 50411, Estonia. E-mail: Sulev.Koks@ut.ee Genes and Immunity (2008) 9, 445–451 & 2008 Macmillan Publishers Limited All rights reserved 1466-4879/08 $30.00 www.nature.com/gene