Psoriasis Susceptibility Locus Research Articles

Investigation of 20 non-HLA (human leucocyte antigen) psoriasis susceptibility loci in Chinese patients with psoriatic arthritis and psoriasis vulgaris

Recently, a number of non-HLA (human leucocyte antigen) psoriasis genetic susceptibility loci have been identified through genome-wide association studies, but data on their association with psoriatic arthritis (PsA) are lacking. To investigate recently identified psoriasis susceptibility loci in a cohort of Chinese patients with PsA, psoriasis vulgaris (PsV) and healthy controls. Twenty single-nucleotide polymorphisms (SNPs) from 20 loci were selected for genotyping in 379 patients with PsA, 595 patients with PsV and 1181 healthy controls using the MassARRAY platform (Sequenom, San Diego, CA, U.S.A.). Data handling, quality control and association were performed using PLINK software, v. 1.07. The Cochran-Armitage trend test was used to test the genotype-phenotype association. PsA showed a significant association with markers at TNIP1 (rs17728338, P = 2.20 × 10(-8)), IL28RA (rs4649203, P = 5.04 × 10(-6)), IL12B (rs2082412, P = 3.82 × 10(-5)), ERAP1 (rs27524, P = 1.25 × 10(-3)), PTTG1 (rs2431697, P = 1.22 × 10(-3)) and GJB2 (rs3751385, P = 1.48 × 10(-3)) when compared with the control group. In PsV a significant association was found for IL28RA (rs4649203, P = 9.53 × 10(-7)), TNIP1 (rs17728338, P = 1.21 × 10(-4)) and ERAP1 (rs27524, P = 1.17 × 10(-3)). The allele frequencies were not statistically different between PsA and PsV except for SNPs at IL12B and ZNF816A with a nominal P-value of 0.04 and 0·01, respectively. This study provides evidence for the involvement of ERAP1, IL28RA, GJB2 and PTTG1 loci in PsA susceptibility and confirmed the previously reported association with PsA and PsV. These results support the hypothesis that genetic aetiology of psoriasis is the same in both PsA and PsV and also support the higher genetic component of PsA than PsV.

Genome-wide linkage scan for psoriasis susceptibility loci in multiplex Tunisian families

Psoriasis is a relapsing chronic inflammatory skin disease affecting all population groups, with a peak prevalence of 3% in northern European and Scandinavian caucasians. Epidemiological studies have implicated a genetic component to psoriasis. In the past 12 years multiple genome-wide linkage analyses have identified putative susceptibility loci on several chromosomes, with a major locus in the major histocompatibility complex region. To investigate the genetic basis of familial psoriasis in the Tunisian population using a genome-wide linkage scan in seven ultiplex psoriatic families from Tunisia. Following single nucleotide polymorphism (SNP) genotyping on the Affymetrix 10K SNP array, we performed nonparametric linkage (NPL) multipoint analyses to identify genotypes and obtain evidence for linkage with psoriasis across the genome. No chromosomal region gave consistent evidence for linkage, providing evidence for genetic heterogeneity in Tunisian psoriasis families. Significant evidence for linkage of psoriasis to chromosome 2p12 was seen in one family. We also identified several regions of tentative psoriasis linkage on chromosomes 2q, 4q, 6p, 11q, 12q, 9q and 13q. One family exhibiting suggestive evidence for linkage to 17q25 (PSORS2) was identified and all affected members harboured a p.Gly117Ser mutation in CARD14 (caspase recruitment domain family, member 14), recently reported to lead to psoriasis in a large family from the U.S.A. Our results support the genetic heterogeneity of psoriasis in the Tunisian population, provide confirmatory evidence for a novel psoriasis locus at chromosome 2p12 and reveal a psoriasis family with a mutation at PSORS2.

Centrosomal Localization of the Psoriasis Candidate Gene Product, CCHCR1, Supports a Role in Cytoskeletal Organization

CCHCR1 (Coiled-Coil α-Helical Rod protein 1), within the major psoriasis susceptibility locus PSORS1, is a plausible candidate gene with the psoriasis associated risk allele CCHCR1*WWCC. Although its expression pattern in psoriatic skin differs from healthy skin and its overexpression influences cell proliferation in transgenic mice, its role as a psoriasis effector gene has remained unsettled. The 5′-region of the gene contains a SNP (rs3130453) that controls a 5′-extended open reading frame and thus the translation of alternative isoforms. We have now compared the function of two CCHCR1 isoforms: the novel longer isoform 1 and the previously studied isoform 3. In samples of Finnish and Swedish families, the allele generating only isoform 3 shows association with psoriasis (P<10−7). Both isoforms localize at the centrosome, a cell organelle playing a role in cell division. In stably transfected cells the isoform 3 affects cell proliferation and with the CCHCR1*WWCC allele, also apoptosis. Furthermore, cells overexpressing CCHCR1 show isoform- and haplotype-specific influences in the cell size and shape and alterations in the organization and expression of the cytoskeletal proteins actin, vimentin, and cytokeratins. The isoform 1 with the non-risk allele induces the expression of keratin 17, a hallmark for psoriasis; the silencing of CCHCR1 reduces its expression in HEK293 cells. CCHCR1 also regulates EGF-induced STAT3 activation in an isoform-specific manner: the tyrosine phosphorylation of STAT3 is disturbed in isoform 3-transfected cells. The centrosomal localization of CCHCR1 provides a connection to the abnormal cell proliferation and offers a link to possible cellular pathways altered in psoriasis.

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.

SummaryTo gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of three genome-wide association studies (GWAS) and two independent datasets genotyped on the Immunochip, involving 10,588 cases and 22,806 controls in total. We identified 15 new disease susceptibility regions, increasing the number of psoriasis-associated loci to 36 for Caucasians. Conditional analyses identified five independent signals within previously known loci. The newly identified shared disease regions encompassed a number of genes whose products regulate T-cell function (e.g. RUNX3, TAGAP and STAT3). The new psoriasis-specific regions were notable for candidate genes whose products are involved in innate host defense, encoding proteins with roles in interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C), and 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.

Resequencing of the IL12B gene in psoriasis patients with the rs6887695/rs3212227 risk genotypes

Background and aimsRecent genomic surveys have identified IL12B as susceptibility locus for psoriasis (Ps). Our aim was to replicate the association between IL12B SNPs and Ps. In addition, we sequenced the IL12B gene in several patients to identify new variants that could explain the disease-risk. ResultsA total of 304 Ps-patients and 422 healthy controls (all Caucasian Spanish) were genotyped for three IL12B polymorphisms. SNP rs6887695 (GG genotype) was significantly associated with Ps (p=0.002; OR=1.60, 95% CI=1.19–2.16). This genotype was also more frequent among patients with severe psoriasis (p=0.03). Sequencing of 30 patients with the risk genotype identified several IL12B reported SNPs. Allele and genotype frequencies for two putative functional variants (rs3213120 and rs3213119) did not differ between patients and controls. ConclusionsOur study confirmed rs6887695 as a risk factor for Ps. No other IL12B variants that could explain this association were found in our patients.

Familial Pityriasis Rubra Pilaris Is Caused by Mutations in CARD14

Pityriasis rubra pilaris (PRP) is a papulosquamous disorder phenotypically related to psoriasis. The disease has been occasionally shown to be inherited in an autosomal-dominant fashion. To identify the genetic cause of familial PRP, we ascertained four unrelated families affected by autosomal-dominant PRP. We initially mapped PRP to 17q25.3, a region overlapping with psoriasis susceptibility locus 2 (PSORS2 [MIM 602723]). Using a combination of linkage analysis followed by targeted whole-exome sequencing and candidate-gene screening, we identified three different heterozygous mutations in CARD14, which encodes caspase recruitment domain family, member 14. CARD14 was found to be specifically expressed in the skin. CARD14 is a known activator of nuclear factor kappa B signaling, which has been implicated in inflammatory disorders. Accordingly, CARD14 levels were increased, and p65 was found to be activated in the skin of PRP-affected individuals. The present data demonstrate that autosomal-dominant PRP is allelic to familial psoriasis, which was recently shown to also be caused by mutations in CARD14.

PSORS2 Is Due to Mutations in CARD14

Psoriasis is a common, immune-mediated genetic disorder of the skin and is associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosomal region 17q25.3-qter after a genome-wide linkage scan in a family of European ancestry with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a Taiwanese family with multiple psoriasis-affected members. In caspase recruitment domain family, member 14 (CARD14), we identified unique gain-of-function mutations that segregated with psoriasis by using genomic capture and DNA sequencing. The mutations c.349G>A (p.Gly117Ser) (in the family of European descent) and c.349+5G>A (in the Taiwanese family) altered splicing between CARD14 exons 3 and 4. A de novo CARD14 mutation, c.413A>C (p.Glu138Ala), was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and compared with wild-type CARD14, the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes. These genes included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, whereas in lesional psoriatic skin, it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the epidermis. We propose that, after a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration, a cycle which is the hallmark of psoriasis.

Abnormal epidermal barrier in the pathogenesis of psoriasis

Almost 2 decades ago, Williams and Elias suggested a unifying concept for the pathogenesis of disorders of cornification, according to which the integrity of the epidermal barrier and its effective function is an important factor in the regulation of epidermal DNA synthesis. Interference with the barrier integrity or function will result in epidermal hyperplasia and may be the primary event leading to hyperproliferative skin diseases, such as psoriasis.We have analyzed alterations to several structures of the epidermal barrier that might be responsible for barrier dysfunction and thus lead to hyperproliferation of the epidermis in an attempt to repair the barrier and, as a result, might be inducers of psoriasis. There are several convincing reports indicating that inhibiting of epidermal transglutaminase may lead to epidermal hyperproliferation and that this stimulus might trigger psoriasis among genetically predisposed patients.Disturbance of epidermal barrier function caused by derangement of lipid or cholesterol or ceramide synthesis leads to increased DNA synthesis and epidermal hyperplasia and as a result might be an inducer of psoriasis. We could find little evidence to show that defective defense of the epidermis or an abnormal response of it to bacteria plays a role in the pathogenesis of psoriasis.Accumulating data indicate that there is an association of psoriasis and mutations of genes within the epidermal differentiation complex, which are crucial for the development, maturation, cornification, cross-linking, and terminal differentiation of the epidermis, called psoriasis susceptibility locus 4.

Heterogeneity of Inflammatory and Cytokine Networks in Chronic Plaque Psoriasis

The clinical features of psoriasis, characterized by sharply demarcated scaly erythematous plaques, are typically so distinctive that a diagnosis can easily be made on these grounds alone. However, there is great variability in treatment response between individual patients, and this may reflect heterogeneity of inflammatory networks driving the disease. In this study, whole-genome transcriptional profiling was used to characterize inflammatory and cytokine networks in 62 lesional skin samples obtained from patients with stable chronic plaque psoriasis. We were able to stratify lesions according to their inflammatory gene expression signatures, identifying those associated with strong (37% of patients), moderate (39%) and weak inflammatory infiltrates (24%). Additionally, we identified differences in cytokine signatures with heightened cytokine-response patterns in one sub-group of lesions (IL-13-strong; 50%) and attenuation of these patterns in a second sub-group (IL-13-weak; 50%). These sub-groups correlated with the composition of the inflammatory infiltrate, but were only weakly associated with increased risk allele frequency at some psoriasis susceptibility loci (e.g., REL, TRAF3IP2 and NOS2). Our findings highlight variable points in the inflammatory and cytokine networks known to drive chronic plaque psoriasis. Such heterogeneous aspects may shape clinical course and treatment responses, and can provide avenues for development of personalized treatments.

Current understanding of human genetics and genetic analysis of psoriasis

During the past 5 years, genome-wide association studies (GWAS), primarily based on single nucleotide polymorphism markers, have identified many loci as potential psoriasis susceptibility regions. These studies appeared to provide strong evidence because the susceptibility genes are involved in the interleukin-23/T-helper 17 axis of psoriasis immunopathogenesis and/or skin barrier functions. However, the "identified" genes only explained a small proportion of psoriasis heritability, although it is known to be comparatively higher than that of other common diseases. GWAS are based on the hypothesis that disease-causing variants are high frequency variants within populations. However, this hypothesis is problematic because deleterious variants such as those predisposing to specific diseases will generally not be maintained by selection pressure throughout human evolution. This issue also affects psoriasis studies. Here, we review the current paradigm shift in human genetic analyses and its implications for detection of psoriasis-causing variants based on linkage analysis and GWAS, except the well-known psoriasis susceptibility locus HLA-C.

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

Characterization of the LPIN2 Gene and its Protein and Examination of its Role in Psoriasis

Psoriasis is a chronic inflammatory skin disease posing a considerable worldwide health problem due to its high prevalence, associated morbidity and high health-care costs. It is a multifactorial “complex” disorder, with compelling evidence for a genetic predisposition. On the other hand, Majeed syndrome, a Mendelian disorder of bone and skin inflammation is caused by homozygous mutations in LPIN2. Many observations have implicated LPIN2 in the genetic etiology of psoriasis, including its position in a psoriasis locus. We identified several non-synonymous SNPs within the LPIN2 in patients with psoriasis that are not present in healthy controls. We hypothesize that the variations in LPIN2 play a role in the susceptibility to development of psoriasis and that LPIN2 is the psoriasis susceptibility locus on 18p. We aim to examine this hypothesis by examining the properties of the wild type and mutant proteins, as well as examining any difference in function between the wild type and mutants. We have obtained custom synthesized cDNA clones encoding the full Lipin2 wild type protein and the six identified mutant proteins (p.K387E, p.S734L, p.A331S, p.L504F, p.P348L, p.E601K). The cDNA clones were subcloned into pYES2 vector for expression in yeast cells (Saccharomyces cerevisiae). Each construct was transformed into Saccharomyces cerevisiae for protein expression. The analysis utilizes SDS Gel Electophoresis and Western Blot. The DNA analysis indicates that each fragment has been correctly cloned into the pYES2 vector. The analyses using SDS Gel Electrophoresis and Western Blot indicate that the Wild type and p.K387E are successfully expressed in S. cerevisiae while p.S734L is expressed in S. cerevisiae but at a lower level. Expression experiments are being done on the 4 remaining mutant proteins. We were successful in artificially expressing the human Lipin2 protein in its different forms in yeast cells. We are currently optimizing the conditions to produce substantial amounts of the proteins to be studied by Circular dichroism to determine the folding patterns. Other methods will be approached to study the function.

The filaggrin null genotypes R501X and 2282del4 seem not to be associated with psoriasis: results from general population study and meta‐analysis

Psoriasis vulgaris could be associated with the filaggrin null genotype since certain known susceptibility loci for psoriasis are shared with susceptibility loci for atopic dermatitis. Furthermore, filaggrin expression is lowered in psoriatic skin lesions but normally expressed in uninvolved skin. So far five relatively small patient-based case-control studies have rejected a possible association between psoriasis and the two most prevalent filaggrin null mutations, 2282del4 and R501X. To reinvestigate a possible association between psoriasis and filaggrin null mutation status by using cross-sectional general population questionnaire data. Also, to perform a meta-analysis including published studies that investigated the relation between filaggrin gene mutations R501X and 2282del4, respectively, and psoriasis vulgaris. Between June 2006 and May 2008, a cross-sectional study was performed in the general population in Copenhagen. A random sample of 7931 subjects aged 18-69 years was invited to participate in a general health examination including a questionnaire and 3471 (43.7%) participated. A total of 3335 (96.1%) individuals were filaggrin genotyped for the 2282del4 and R501X mutations. A meta-analysis was undertaken to investigate the relation between filaggrin gene mutations and psoriasis vulgaris. The prevalence of self-reported psoriasis was 6.7% among the 3240 respondents. The prevalence of the R501X and 2282del4 filaggrin null genotypes was 9.3% in subjects who reported psoriasis and 8.0% in subjects who did not report psoriasis (OR = 1.28; 95% CI = 0.74-1.89; P = 0.78). The meta-analysis found no association between the filaggrin null genotypes R501X and 2282del4 and psoriasis (OR = 1.04; 95% CI = 0.81-1.35). Psoriasis was not associated with the R501X and 2282del4 filaggrin null genotypes in a general population study and in a meta-analysis on published studies.

Corneodesmosomes and corneodesmosin: from the stratum corneum cohesion to the pathophysiology of genodermatoses

Corneodesmosin (CDSN) was identified 20 years ago by raising monoclonal antibodies against human plantar stratum corneum. The protein is specific to corneodesmosomes, cell-junction structures that, in humans, are found in the epidermis, the hard palate epithelium, and the inner root sheath of the hair follicles. Synthesized by the granular keratinocytes and secreted via the lamellar bodies, CDSN is incorporated into the desmoglea of the desmosomes, shortly before their transformation into corneodesmosomes during cornification. CDSN displays adhesive properties, mostly attributable to its N-terminal glycine-rich domain, and is sequentially proteolyzed as corneocytes migrate towards the skin surface prior to desquamation. The recent inactivation of Cdsn in mice induced a lethal epidermal barrier disruption and hair follicle degeneration, related to corneodesmosome dysfunction. That confirmed the essential role of the protein in maintaining integrity of the epidermis and the hair follicle. The CDSN gene is located in PSORS1, the major psoriasis susceptibility locus on the chromosome 6, but to date its involvement in the disease pathophysiology is not clear. By contrast, two different monogenic diseases associated with nonsense mutations in CDSN, were recently identified. First, hypotrichosis simplex of the scalp in which mutated CDSN accumulates in the dermis and forms amyloid deposits; then, peeling skin disease in which the genetic defect induces dyscohesion of the stratum corneum, responsible for abnormal desquamation and increased skin penetration of allergens.

Characterization of the LPIN2 gene and its protein and examination of its role in psoriasis

Psoriasis is a chronic inflammatory skin disease posing a considerable world-wide health problem due to its high prevalence, associated morbidity and high health-care costs. It is a multifactorial “complex” disorder, with compelling evidence for a genetic predisposition. Majeed syndrome is a Mendelian disorder with a consistent phenotype and its causative gene can be examined for its role in the more common bone and skin inflammatory disorders of complex etiology. Majeed syndrome is caused by mutations in LPIN2. Many observations have implicated LPIN2 in the genetic etiology of psoriasis. Based on these observations, we hypothesize that variations in LPIN2 play a role in the susceptibility to development of psoriasis and that LPIN2 is the psoriasis susceptibility locus on 18p. In our previous study, we identified 6 coding variants that may be associated with psoriasis due to the fact that they change evolutionary conserved amino acids and they are present in the general population at a very low allele frequency. However, the ultimate evidence of their causation of the phenotype is to prove that there is a change in protein properties or function with the molecular variations. One of the aims of the current work is to shed light on whether each identified LPIN2 mutation has an effect on the integrity of the properties of the Lipin2 protein and therefore its function. The wide type and six different cDNA LPIN2 clones, each harboring one of the six described variations were successfully synthesised after codon optimisation for maximum expression in yeast. The LPIN2 gene and two mutants were excised from its original construct and inserted into similarly digested pYES2. The newly formed constructs were transformed into competent cells of Saccharomyces cerevisiae for protein expression. Our preliminary analyses using SDS gel electrophoresis and Western blot indicate that the wild type and the two mutants are expressed in S. cerevisiae but at a low level. Optimization of the expression as well as expression of these genes in different expression system is being carried out. The recombinant protein of the wild type LPIN2 and the two mutants will be subjected to circular dichroism and fluorescence measurements to study the effect of each mutant on the folding and therefore the function of the protein.

Gene from a Psoriasis Susceptibility Locus Primes the Skin for Inflammation

Psoriasis is a common complex genetic disease characterized by hyperplasia and inflammation in the skin; however, the relative contributions of epidermal cells and the immune system to disease pathogenesis remain unclear. Linkage studies have defined a psoriasis susceptibility locus (PSORS4) on 1q21, the epidermal differentiation complex, which includes genes for small S100 calcium-binding proteins. These proteins are involved in extracellular and intracellular signaling during epithelial host defense, linking innate and adaptive immunity. Inflammation-prone psoriatic skin constitutively expresses elevated concentrations of S100A7 (psoriasin) and S100A15 (koebnerisin) in the epidermis. Here, we report that genetically modified mice expressing elevated amounts of doxycycline-regulated mS100a7a15 in skin keratinocytes demonstrated an exaggerated inflammatory response when challenged by exogenous stimuli such as abrasion (Koebner phenomenon). This immune response was characterized by immune cell infiltration and elevated concentrations of T helper 1 (T(H)1) and T(H)17 proinflammatory cytokines, which have been linked to the pathogenesis of psoriasis and were further amplified upon challenge. Both inflammation priming and amplification required mS100a7a15 binding to the receptor of advanced glycation end products (RAGE). mS100a7a15 potentiated inflammation by acting directly as a chemoattractant for leukocytes, further increasing the number of inflammatory cells infiltrating the skin. This study provides a pathogenetic psoriasis model using a psoriasis candidate gene to link the epidermis and innate immune system in inflammation priming, highlighting the S100A7A15-RAGE axis as a potential therapeutic target.

Genome-wide association analysis identifies three psoriasis susceptibility loci.

To identify novel psoriasis susceptibility loci, we carried out a meta-analysis of two recent genome-wide association studies 1,2, yielding a discovery sample of 1,831 cases and 2,546 controls. 102 of the most promising loci in the discovery analysis were followed up in a three-stage replication study using 4,064 cases and 4,685 controls from Michigan, Toronto, Newfoundland, and Germany. Association at a genome-wide level of significance for the combined discovery and replication samples was found for three genomic regions. One contains NOS2 (rs4795067, p = 4 × 10−11), another contains FBXL19 (rs10782001, p = 9 × 10−10), and a third contains PSMA6 and NFKBIA (rs12586317, p = 2 × 10−8). All three loci were also strongly associated with the subphenotypes of psoriatic arthritis and purely cutaneous psoriasis. Finally, we confirmed a recently identified3 association signal near RNF114.

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

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 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). 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.

Association analyses identify six new psoriasis susceptibility loci in the Chinese population

We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10⁻⁸) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10⁻²¹) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10⁻³ and P = 7.9 × 10⁻³, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10⁻³ and P = 1.5 × 10⁻³, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.

Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2

Psoriasis is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation, the most common form of which is psoriasis vulgaris (PsV). We present a genome-wide association analysis of 2,339,118 SNPs in 472 PsV cases and 1,146 controls from Germany, with follow-up of the 147 most significant SNPs in 2,746 PsV cases and 4,140 controls from three independent replication panels. We identified an association at TRAF3IP2 on 6q21 and genotyped two SNPs at this locus in two additional replication panels (the combined discovery and replication panels consisted of 6,487 cases and 8,037 controls; combined P = 2.36 × 10⁻¹⁰ for rs13210247 and combined P = 1.24 × 10⁻¹⁶ for rs33980500). About 15% of psoriasis cases develop psoriatic arthritis (PsA). A stratified analysis of our datasets including only PsA cases (1,922 cases compared to 8,037 controls, P = 4.57 × 10⁻¹² for rs33980500) suggested that TRAF3IP2 represents a shared susceptibility for PsV and PsA. TRAF3IP2 encodes a protein involved in IL-17 signaling and which interacts with members of the Rel/NF-κB transcription factor family.