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Generalized pustular psoriasis is a severe psoriatic subtype characterized by epidermal neutrophil infiltration. Although variants in IL36RN and MPO have been shown to affect immune cells, a systematic analysis of neutrophils and PBMC subsets and their differential gene expression dependent on MPO genotypes was not performed yet. We assessed the transcriptomes of MPO-deficient patients using single-cell RNA sequencing of PBMCs and RNA sequencing of neutrophils in a stable disease state. Cell-type annotation by multimodal reference mapping of single-cell RNA-sequencing data was verified by flow cytometry of surface and intracellular markers; the proportions of CD4

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP’s pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.

Background Syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) and chronic recurrent multifocal osteomyelitis (CRMO) present two diseases of a dermatologic and rheumatologic spectrum that are variable in manifestation und therapeutic response. Genetic risk factors have long been assumed in both diseases, but no single reliable factor has been identified yet. Therefore, we aimed to clinically characterize a patient group with syndrome of synovitis acne pustulosis hyperostosis osteitis (SAPHO) (n = 47) and chronic recurrent multifocal osteomyelitis (CRMO)/ chronic non-bacterial osteomyelitis (CNO) (n = 9) and analyze a CRMO candidate gene. Methods Clinical data of all patients were collected and assessed for different combinations of clinical symptoms. SAPHO patients were grouped into categories according to the acronym; disease-contribution by pathogens was evaluated. We sequenced coding exons of FBLIM1. Results Palmoplantar pustular psoriasis (PPP) was the most common skin manifestation in CRMO/CNO and SAPHO patients; most SAPHO patients had sterno-costo-clavicular hyperostosis. The most common clinical category of the acronym was S_PHO (n = 26). Lack of pathogen detection from bone biopsies was more common than microbial isolation. We did not identify autosomal-recessive FBLIM1 variants. Conclusions S_PHO is the most common combination of symptoms of its acronym. Genetic analyses of FBLIM1 did not provide evidence that this gene is relevant in our patient group. Our study indicates the need to elucidate SAPHO’s and CRMO/CNO’s pathogenesis.

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted. Funding Agencies|Medical Research Council (MRC) Stratified Medicine award [MR/L011808/1]; Psoriasis Association [RG2/10]; MRC Clinical Training Fellowship [MR/L001543/1]; NIHR Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust; Kings College London; NIHR Biomedical Research Centre at South London; Maudsley NHS Foundation Trust; Maudsley Charity [980]; Guys and St Thomass Charity [STR130505]; MRC grant [G0000934]; Wellcome Trust grant [068545/Z/02]; German Federal Ministry of Education and Research (BMBF) [01ZX1306A]; PopGen Biobank (Kiel, Germany) [01EY1103]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health; BMBF; State of Bavaria; Munich Center of Health Sciences (MC Health); Ludwig-Maximilians-Universitat, of LMUinnovativ; BMBF [01ZZ9603, 01ZZ0103, 01ZZ0403, 03152061A, 03Z1CN22]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg -West Pomerania; network Greifswald Approach to Individualized Medicine (GANI MED); Federal State of Mecklenburg West Pomerania; BMBF Metarthros grant [01EC1407A]; National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; GAIN award from the Foundation for the National Institutes of Health; Ann Arbor Veterans Affairs Hospital; Taubman Medical Research Institute; International Psoriasis Council

Generalized pustular psoriasis (GPP) is a potentially life-threatening disease that can be attributed to mutations in IL36RN in a subgroup of patients. In small trials, interleukin (IL)-17A and IL-17RA antagonists have been shown to be effective in patients with generalized pustular psoriasis in Japan. We identified seven patients who received the IL-17A antagonists secukinumab (six cases) or ixekizumab (one case) in two dermatological centers. All patients showed a good or excellent clinical response. Anti-IL-17A therapy was well tolerated and ongoing in all patients after an average therapy duration of 12.9 months. Analysis of IL36RN mutation status was performed in six patients, one patient carried a heterozygous mutation, while the other five patients did not show a mutation in IL36RN. This is the first report of a successful treatment of GPP patients without IL36RN mutations responding to anti-IL-17A therapy.

Background: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). Objective: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. Methods: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. Results: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. Conclusion: sThe identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN. What's already known about this topic? The genes IL36RN, CARD14 and AP1S3 have been implicated in pustular skin disease with IL36RN having a major role. Most studies have analysed variants in different genes separately. Significant subsets of patients with a pustular skin disease carry a single heterozygous mutation in IL36RN, leaving unanswered whether and how the variant is disease-contributing. What does this study add? Intragenic copy-number variants or noncoding mutations in carriers of single IL36RN mutations were not found. In total, 15% of patients with generalized pustular psoriasis (GPP) with IL36RN mutations carried variants in CARD14 or AP1S3, providing evidence for a complex inheritance. Lack of causal /disease-contributing variants in 64% of GPP patients suggests a role for other, not yet identified genes. Genotype-phenotype correlation did not reveal significant correlations aside from the presence of IL36RN mutations with age at onset. What is the translational message? This study of three genes provides evidence that the inheritance of GPP is more complex than previously understood. The role of known genes in GPP is rather limited, as almost two-thirds of patients do not carry a variant in any of these genes. In palmoplantar pustular psoriasis, the percentage of noncarriers is even lower. Further genetic studies will reveal the diseases' pathogenesis and provide a basis to use/develop more specific treatments. Linked Comment:Capon. Br J Dermatol 2018;178:589-590 Respond to this article

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹⁷). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²⁰, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.

Contains fulltext : 89438.pdf (Publisher’s version ) (Closed access) Recently, a deletion of two late cornified envelope (LCE) genes within the epidermal differentiation complex on chromosome 1 was shown to be overrepresented in 1,426 psoriasis vulgaris (PsV) patients of European ancestry. In this study, we report a confirmation of this finding in 1,354 PsV patients and 937 control individuals of German origin. We found an allele frequency of the deletion of 70.9% in PsV patients and of 64.9% in control individuals (chi(2)=17.44, P=2.97 x 10(-5), odds ratio (95% confidence interval)=1.31 (1.15-1.48)). The overall copy number of the two LCE genes had no influence on the age of onset, but we observed a dosage effect at the genotype level. There was no evidence of statistically significant interaction with copy number of the beta-defensin cluster on 8p23.1 or with an IL-23R pathway variant in a combined data set of German and Dutch individuals, whereas evidence for interaction with the PSORS1 risk allele in German individuals was marginal and did not remain significant after correction for multiple testing. Our study confirms the recently published finding that the deletion of the two LCE genes is a susceptibility factor for PsV with dosage effect, while, because of power limitation, no final conclusion regarding interaction with other PsV risk factors can be made at this stage. 01 april 2010

Psoriasis is an immune-mediated skin disorder that is inherited as a multifactorial trait. Linkage studies have clearly identified a primary disease susceptibility locus lying within the major histocompatibility complex (MHC), but have generated conflicting results for other genomic regions. To overcome this difficulty, we have carried out a genome-wide association scan, where we analyzed more than 408,000 SNPs in an initial sample of 318 cases and 288 controls. Outside of the MHC, we observed a single cluster of disease-associated markers, spanning 47 kb on chromosome 20q13. The analysis of two replication data sets confirmed this association, with SNP rs495337 yielding a combined P-value of 1.4 x 10(-8) in an overall sample of 2679 cases and 2215 controls. Rs495337 maps to the SPATA2 transcript and is in absolute linkage disequilibrium with five SNPs lying in the adjacent ZNF313 gene (also known as RNF114). Real-time PCR experiments showed that, unlike SPATA2, ZNF313 is abundantly expressed in skin, T-lymphocytes and dendritic cells. Furthermore, an analysis of the expression data available from the Genevar database indicated that rs495337 is associated with increased ZNF313 transcripts levels (P = 0.003), suggesting that the disease susceptibility allele may be a ZNF313 regulatory variant tagged by rs495337. Homology searches indicated that ZNF313 is a paralogue of TRAC-1, an ubiquitin ligase regulating T-cell activation. We performed cell-free assays and confirmed that like TRAC-1, ZNF313 binds ubiquitin via an ubiquitin-interaction motif (UIM). These findings collectively identify a novel psoriasis susceptibility gene, with a putative role in the regulation of immune responses.

Objective Single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor gene TNF at positions −238 and −308 have been associated with psoriasis vulgaris and psoriatic arthritis (PsA). The strong linkage disequilibrium (LD) at chromosome region 6p21, a region known to harbor risk factors for psoriasis susceptibility (PSORS1) other than just SNPs of the TNF gene, renders the interpretation of these findings difficult. The aim of this study was to analyze several SNPs of the TNF gene and its neighboring LTA gene for independent and dependent carriage of the PSORS1 risk allele. Methods SNPs in the promoter of the TNF (−238G/A, −308G/A, −857C/T, and −1031T/C), LTA (+252A/G), TNLFRSF1A (+36A/G), and TNLFRSF1B (+676T/G) genes were genotyped in 375 psoriasis patients, 375 PsA patients, and 376 controls. The Trp- Trp-Cys-Cys haplotype of the CCHCR1 gene (CCHCR1*WWCC) was used as an estimate of the risk allele PSORS1. Results Whereas we were able to confirm the previously described strong association of allele TNF*-238A with psoriasis, our study revealed that this association was completely dependent on carriage of the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without joint involvement, a strong association with the allele TNF*-857T (odds ratio 1.956 [95% confidence interval 1.334–2.881]; corrected P = 0.0025) was also detected in patients negative for the PSORS1 risk allele. Conclusion Our results indicate that there are genetic differences between psoriasis vulgaris patients with and without joint manifestations. While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect LD with PSORS1, TNF*-857T may represent a risk factor for PsA that is independent of the PSORS1 allele.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case-control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8(+) memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.

The gene for solute carrier family 12 member A8 has recently been proposed as a candidate gene for psoriasis susceptibility (PSORS5) on chromosome 3q based on association of five single nucleotide polymorphisms (SNP) in Swedish patients. To investigate whether this locus is relevant for German psoriasis vulgaris (PsV) patients, we analyzed a group of 210 trios and a case-control group including 375 patients. Based on our investigation of the linkage disequilibrium (LD) structure of SLC12A8, we assayed 35 haplotype tag SNP and grouped them into nine LD-blocks. In the case-control study, we detected an association for six SNP and three LD-based haplotypes. Association was strongest for ss35527511 (chi2 = 11.224, p = 0.0008) and haplotype E-2 (chi2 = 11.788, p = 0.00059) and independent of the presence of an HLA-associated PSORS1 risk allele. Through extended haplotype analysis, we could show that two independent association signals exist in SLC12A8, suggesting allelic heterogeneity. None of the SNP showed association in trios, apart from a weak association of rs2228674 (transmission disequilibrium test statistics p = 0.048), probably due to insufficient power. We conclude that SLC12A8 is a susceptibility locus for PsV. In order to establish the exact nature of this association, efforts to identify the disease-causing variants are ongoing.

To determine whether the three common independent sequence variants of the putative pleiotropic non-MHC autoimmune gene CARD15 influence disease susceptibility in large German cohorts of patients with psoriatic arthritis and psoriasis vulgaris, before and after stratification to HLA-C.DNA was obtained from 375 patients with psoriatic arthritis, 281 patients with psoriasis vulgaris without joint involvement, and 376 controls. The three variants of the CARD15 gene (R702W, G908R, leu1007fsinsC), and two single nucleotide polymorphisms of the HCR gene (HCR-325, HCR-2327) for HLA-C stratification were genotyped using allelic discrimination Taqman assays.No significant differences in genotype frequencies were observed between controls and either the psoriatic arthritis or the psoriasis vulgaris patient population, even after stratification to HLA-C in both patient cohorts, or to the type of joint involvement within the psoriatic arthritis group.The lack of genetic association between the most common Crohn's disease alleles of the CARD15 gene and psoriatic joint disease on large cohorts of white patients does not support a recently claimed role for CARD15 as the first non-MHC susceptibility gene in the pathogenesis of psoriatic arthritis, but confirms and extends previous studies in the case of psoriasis vulgaris.

A DNA variant, rs734232, altering a RUNX1 binding site was recently reported as susceptibility allele at PSORS2 (17q25) in cohorts of psoriasis patients from the US. A testing of this variant in psoriasis patients from Germany did not confirm this association in 300 trios nor in two case-control studies with 281 patients with psoriasis vulgaris and 375 patients with psoriatic arthritis, respectively. These results fail to support rs734232 as a psoriasis susceptibility factor in German psoriasis patients.

To follow up the novel psoriasis susceptibility region on chromosome 19 (PSORS6), we performed an association scan for psoriasis vulgaris using 45 evenly spaced DNA microsatellite markers. For this study, a new independent sample of 210 nuclear psoriasis families (trio design) from Northern Germany was recruited. We used the family based association test (FBAT) for an association scan over the chromosome 19 region encompassing 50.8 cM. We obtained a positive association for the markers D19S922 (allele 5, P = 0.008) and D19S916 (allele 13, P = 0.016), which correspond to the peak of the region identified in a previously performed scan. We identified two novel regions by a single marker, each showing negative association at D19S917 on 19p13.1 (allele 8, P = 0.0034) and at D19S425 (allele 9, P = 0.0005), compatible with the hypothesis of protective loci. These two novel regions were explored in more detail using novel microsatellite markers at an average distance of 100 kb. A separate analysis distinguishing between familial (n = 137) and sporadic (n = 73) psoriasis families showed that the familial trios contribute strongly in the region around D19S425 (P = 0.004), while the comparably small subset of 73 sporadic trios has a stronger effect at the locus around D19S917 (P = 0.026). These studies confirm the existence of a psoriasis susceptibility locus on chromosome 19 and give first evidence for the existence of both susceptible and protective loci in this region. Analysis of a dense marker set from these refined regions will eventually allow identification of the underlying susceptibility alleles.

Introduction Psoriasis susceptibility locus 4 (PSORS4) is a susceptibility locus for psoriasis vulgaris (PsV), a common inflammatory, hyperproliferative skin disorder. Recently, a deletion of 2 late cornified envelope ( LCE ) genes within epidermal differentiation complex on chromosome 1 was shown to be enriched in 1426 patients with PsV, suggesting compromised barrier function in deletion carriers. This genetic association was subsequently confirmed in a German cohort. Methods In order to investigate whether this variant also predisposes to psoriatic arthritis (PsA), this deletion and 3 single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium with it were genotyped in a case-control cohort of 650 patients and 937 control individuals of German origin. Results LCE deletion frequency did not significantly differ between patients with PsA and controls (65.0% vs 65.5%). Similarly, no evidence for association to the three SNPs was observed. Discussion This is the first non-human leucocyte antigen (HLA) risk factor predisposing only to skin type of psoriasis, supporting the concept of partially overlapping but different aetiological factors underlying skin and joint manifestations.

Background Psoriatic arthritis (PsA) is an inflammatory arthritis that is associated with psoriasis. Although the majority of PsA genetic risk loci identified also confer risk for psoriasis, we have recently reported evidence of loci that are associated with PsA and not psoriasis, including an association at the IL23R locus which is also independent of a psoriasis variant at the same locus. Methods The PsA-specific SNP rs12044149, and the psoriasis SNP rs9988642 at the IL23R locus were genotyped in a cohort of 914 PsA cases and 6,945 controls from Spain, Crete, Germany and the UK, with the Life Technologies QuantStudio genotyping platform. Association testing was carried out using PLINK, and a meta-analysis was performed with PsA Immunochip data (1,962 cases, 8,923 controls). Genotype data was also available from the psoriasis WTCCC2 study (excluding known PsA, n=1,784) to compare effect sizes between PsA and psoriasis using multinomial logistic regression in Stata, and to directly compare PsA and psoriasis genotypes. Credible SNP sets were calculated for the PsA and psoriasis IL23R associations using the Bayesian refinement method, and functionally annotated. Results We replicated the association rs12044149 with PsA ( P =4.03x10 –6 ), which remained significant when conditioning upon the psoriasis variant, rs9988642 ( P cond =4.86x10 –6 ), and reached genome-wide significance during meta-analysis of the combined PsA dataset ( P meta =4.76x10 –20 ). Only a modest association was found for rs9988642 ( P =0.04), with no genome-wide significance found during meta-analysis ( P =4.61x10 –4 ). Within the psoriasis dataset, this association remained significant when conditioning upon rs12044149 ( P =1.0x10 –07 vs. P cond =1.63x10 –5 ). Effect estimates for rs12044149 were significantly different between PsA and psoriasis ( P =2.0x10 –3 ), and direct comparison of genotypes for PsA and psoriasis found the risk allele to be significantly increased in PsA ( P =4.52x10 –4 , OR=1.3). Credible SNPs for rs12044149 mapped to promoter and enhancer regions within memory CD8 + T cells, which we have previously reported to be critical for PsA. Conclusions We have successfully replicated a PsA-specific (associated with PsA but not psoriasis) risk variant at the IL23R locus in an independent cohort, confirming rs12044149 to be distinct from rs9988642 (r 2 =0.02). This gives five PsA-specific associations that have now been identified. Disclosure of Interest None declared

OBJECTIVE: Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome-wide significance levels of association in the initial analysis. METHODS: Twenty-one of 22 single-nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris. RESULTS: Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 × 10(-8) by Cochran-Mantel-Haenszel test and an odds ratio (OR) of 1.24 (95% confidence interval [95% CI] 1.15-1.33). Further analyses based on linkage disequilibrium (LD) at RUNX3 refined the most significant association to an LD block located in the first intron of one isoform. Weaker evidence for association was detected in German patients with psoriasis vulgaris (P = 5.89 × 10(-2) ; OR 1.13 [95% CI 1.00-1.28]), indicating a role in the skin manifestations of psoriasis. CONCLUSION: Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondyloarthritis, although its risk allele is independent from the one for PsA. RUNX-3 is involved in CD8+ T lymphocyte differentiation and is therefore a good candidate for involvement in PsA and psoriasis vulgaris as T cell-mediated diseases.

Objective The strongest susceptibility locus of psoriatic arthritis (PsA) is within the major histocompatibility complex (MHC) region (psoriasis susceptibility region 1, or PSORS1), and HLA–Cw*06:02 has been reported as the PSORS1 susceptibility allele. Non-HLA genes within the MHC region have also been implicated in PsA, but because of the strong linkage disequilibrium at chromosome 6p21, it is difficult to make a distinction between susceptibility alleles and linked markers. Recent studies have demonstrated that the association between PsA and the tumor necrosis factor (TNF) promoter polymorphism TNF*-857 is independent of PSORS1. The aim of this study was to replicate the independent association of TNF*-857 in patients with PsA. Methods A total of 909 patients with PsA and 1,315 healthy controls originating from the UK, Germany, and Italy were typed for TNF*-857 and for the estimated risk alleles of HLA–Cw*06:02. Results Overall, the results of genotyping in these 3 case–control cohorts replicated the finding that the frequency of carriers of TNF*-857 TT/CT who were negative for the PSORS1 risk allele was significantly higher among patients with PsA compared with control subjects (30% versus 21%; P = 9.17 × 10−5). Conclusion The results of this collaborative study indicate that TNF*-857T is a susceptibility allele for PsA independent of the PSORS1 allele.

Contains fulltext : 96094.pdf (Publisher’s version ) (Closed access) A multicenter meta-analysis including data from 9,389 psoriasis patients and 9,477 control subjects was performed to investigate the contribution of the deletion of genes LCE3C and LCE3B, involved in skin barrier defense, to psoriasis susceptibility in different populations. The study confirms that the deletion of LCE3C and LCE3B is a common genetic factor for susceptibility to psoriasis in the European populations (OR(Overall) = 1.21 (1.15-1.27)), and for the first time directly demonstrates the deletion's association with psoriasis in the Chinese (OR = 1.27 (1.16-1.34)) and Mongolian (OR = 2.08 (1.44-2.99)) populations. The analysis of the HLA-Cw6 locus showed significant differences in the epistatic interaction with the LCE3C and LCE3B deletion in at least some European populations, indicating epistatic effects between these two major genetic contributors to psoriasis. The study highlights the value of examining genetic risk factors in multiple populations to identify genetic interactions, and indicates the need of further studies to understand the interaction of the skin barrier and the immune system in susceptibility to psoriasis.

Contains fulltext : 89179.pdf (Publisher’s version ) (Closed access) To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 x 10 and two loci with a combined P < 5 x 10). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 x 10). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis. 01 november 2010

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

Variants in two genes of the IL-23 receptor (R) pathway have recently been shown to be associated with psoriasis vulgaris (PV). We were interested whether the risk conferred by these variants differs between psoriatic skin and joint disease. Four variants of the IL12B and IL23R genes were analyzed in 1,114 PV patients, 748 patients with psoriatic arthritis (PA) and 937 healthy controls before and after stratification for the major psoriasis risk allele at psoriasis susceptibility locus 1 ( PSORS1 ). For both PA and PV, we detected the strongest association with two IL12B single-nucleotide polymorphisms and the corresponding haplotype as reflected by minimal P -values of 10 -7 and highest odds ratios of 1.50 (1.28–1.75) for rs6887695 in PA patients and 1.50 (1.27–1.76) for rs3212227 in the PV cohort, respectively. For IL23R , only rs11209026 showed an association. The results remained significant after correction for multiple testing. No difference was observed after stratification for the PSORS1 risk allele. While confirming recent reports on variants of the IL-23R pathway as susceptibility factors for PV, our study is the first to extend analysis of both genes to PA. However, our results indicate that these variants are not specific risk factors for arthritis, but relevant for susceptibility to psoriasis in general.

Contains fulltext : 71309.pdf (Publisher’s version ) (Closed access) Psoriasis is a common inflammatory skin disease with a strong genetic component. We analyzed the genomic copy number polymorphism of the beta-defensin region on human chromosome 8 in 179 Dutch individuals with psoriasis and 272 controls and in 319 German individuals with psoriasis and 305 controls. Comparisons in both cohorts showed a significant association between higher genomic copy number for beta-defensin genes and risk of psoriasis.

The anti-inflammatory cytokine interleukin (IL)-10 is considered to play a major role in the pathophysiology of psoriasis, which is characterized by an IL-10 deficiency. Systemic administration of IL-10 has been shown to be an effective therapy for psoriasis. The IL-10 promoter region contains a highly polymorphic microsatellite (IL10.G) and in a recent case-control study the IL10.G13 (144 bp) allele was found to be associated with familial early onset psoriasis (type 1 psoriasis) having a susceptible effect.As it is essential in multifactorial diseases to replicate findings before definite conclusions can be drawn, we decided to perform a follow-up study and to follow a genetic approach analysing allele transmission in families with a positive family history of psoriasis.We studied 137 nuclear families (trio-design) comprising 456 individuals and genotyped the IL10.G marker. For comparison we also genotyped the microsatellite tn62 as a reference marker of the major psoriasis susceptibility locus on chromosome 6p21 (PSORS1). In the present study allele transmission was evaluated using the family-based association test (FBAT) and GENEHUNTER 2.0 based on the transmission/disequilibrium test.The G13 allele (144 bp) had a frequency of 24%, was present in 88 families and clearly showed an even transmission (FBAT, P = 0.753). In contrast, allele 3 (IL10.G9) (136 bp) had a frequency of 39%, was present in 110 families and was transmitted in 43 trios and remained untransmitted in 67 trios (FBAT, P = 0.026), thus showing preferential nontransmission. For the HLA-linked tn62-marker we obtained a P-value of 0.00027 for allele 4 in the same study group.In conclusion, we failed to confirm the susceptible effect of the G13 allele, but provide the first data for a protective effect of allele 3 (IL10.G9) for familial psoriasis. Our results suggest that the IL10.G polymorphism is not a major locus, but acts as a minor locus.

Poster presentation Background Single nucleotide polymorphisms (SNPs) of the TNF gene at positions -238 and -308 have earlier been associated with psoriasis vulgaris and psoriatic arthritis (PsA). However, a strong linkage disequilibrium at the chromosomal region 6p21 renders the interpretation of these findings difficult since also other risk factors for psoriasis (PSORS1) than SNPs of the TNF gene have bee mapped to that particular region. Therefore, in this study several SNPs of the TNF gene and of its neighbouring lymphotoxin alpha (LTA) gene were analysed independently and dependently on carrying the PSORS1 risk allele. Methods SNPs in the promoter of the TNF gene (-238G/A, -308G/A, -857C/T, -1031T/C), and one SNP of the LTA gene (+252A/G), of the TNLFRSF1A gene (+36A/G) and of the TNLFRSF1B gene (+676T/G), respectively, were genotyped in 375 psoriasis patients, 375 PsA patients, and 376 controls. The tryptophan–tryptophan–cysteine–cysteine haplotype of the CCHCR1 gene (CCHCR1*WWCC) was used to estimate the genetic impact of the PSORS1 risk allele. Results Whereas an earlier-described association of allele TNF*-238A with psoriasis could be confirmed, our study revealed that this association was completely dependent on concomitant carriage of the PSORS1 risk allele. For PsA, but not psoriasis vulgaris without joint manifestations, strong association with the allele TNF*-857T was detected (OR = 1.956; P value corrected for multiple testing, Pcorr = 0.0025) also in patients negative for the PSORS1 risk allele. Conclusion Our results indicate genetic differences between psoriasis vulgaris patients with and without joint manifestation. While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect linkage disequilibrium with PSORS1, TNF*-857T may represent a risk factor for PsA independent of PSORS1. A potential pathophysiologic relevance of the elucidated genetic association is further suggested by previously reported experimental evidence for a functional impact of the respective TNF polymorphism on TNFalpha expression levels.

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense. © 2012 Nature America, Inc. All rights reserved.