Characterisation of psoriasis susceptibility locus 6 (PSORS6) in patients with early onset psoriasis and evidence for interaction with PSORS1.

BACKGROUND: Psoriasis is a genetically complex, chronic inflammatory skin disease. The authors have previously identified a susceptibility locus on chromosome 19p13 (PSORS6). METHODS AND RESULTS: In a follow-up linkage disequilibrium (LD) study in an independent family based cohort, the authors found evidence for association to a newly discovered microsatellite at this locus (D19SPS21, p<5.3x10(-5)). An LD based association scan in 300 trios revealed association to several single, single nucleotide polymorphisms (SNPs) in one LD block. When the authors stratified this cohort for carrying the PSORS1 risk allele at the HLA-C locus, evidence for association became much stronger at single SNP and haplotype levels (p values between 1.0x10(-4) and 8.0x10(-4)). In a replication study of 1114 patients and 937 control individuals, evidence for association was also observed after stratification to the PSORS1 risk allele. In both study groups, logistic regression showed evidence for interaction between the risk alleles at PSORS1 and PSORS6. Best p values for rs12459358 in both study groups remained significant after correction for multiple testing. The associated LD block did not comprise any known genes. Interestingly, an adjacent gene, MUC16, coding for a large glycosylated protein expressed in epithelia and of unknown function, could be shown to be also expressed in tissues relevant for pathogenesis of psoriasis such as skin and thymus. Immunohistochemical analyses of skin revealed focal staining for MUC16 in suprabasal epidermal cells. Further functional studies are required to clarify its potential role in psoriasis and identify the causal variant(s) at this locus. CONCLUSION: The data establish PSORS6 as a confirmed psoriasis susceptibility locus showing interaction with PSORS1.

Evidence for susceptibility determinant(s) to psoriasis vulgaris in or near PTPN22 in German patients.

INTRODUCTION: Variant R620W of protein tyrosine phosphatase non-receptor type 22 (PTPN22) has consistently been reported as a susceptibility factor for several autoimmune diseases. We investigated its role in susceptibility to psoriasis, the relevance of possibly other disease-causing variants, and interdependency of the major risk factor for psoriasis at PSORS1. METHODS: R620W was tested in a case-control study initially with 375 German patients and then with an enlarged sample of an additional 418 patients. Analyses were extended to linkage disequilibrium (LD) based haplotypes. Potential interaction between risk haplotypes of PTPN22 and the PSORS1 associated risk allele was tested by regression analysis. PTPN22 coding sequence was determined in 20 patients carrying the risk haplotype. Association and regression analysis were also performed in the extended case-control study. RESULTS: R620W was not associated in either case-control study, while significant association (corrected for multiple testing) with one haplotype (C-4) of the LD block encompassing PTPN22 as well with another haplotype (B-3) within an adjacent telomeric LD block was detected. No evidence for interaction between risk haplotype C-4 and the PSORS1 associated risk allele was found. Sequencing excluded other coding variants within PTPN22 as a basis for association findings. Analysis of the extended study group confirmed association for haplotypes B-3 and C-4 and independence of risk haplotypes C-4 and PSORS1. DISCUSSION: We exclude a major role of *620W in German psoriasis patients but suggest that other susceptibility determinant(s) within non-coding regions of PTPN22 or its proximity might exist acting independently of the major PSORS1 risk factor.