Best Practice & Research Clinical Rheumatology 28 (2014) 673e685

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Genetics of psoriatic arthritis Darren D. O'Rielly c, 1, Proton Rahman a, b, * a

Eastern Health, Memorial University, 154 LeMarchant Rd., St. John's, Newfoundland A1C 5B8, Canada St. Clare's Mercy Hospital, St. John's, Newfoundland A1C 5B8, Canada c Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, Health Sciences Centre, Rm. 1 J440, St. John's, NL A1B 3V6, Canada b

a b s t r a c t Keywords: Genetics Candidate genes GWAS Spondyloarthritis Psoriatic arthritis Psoriasis MHC genes Th17 cell signalling pathways

Spondyloarthritis (SpA) represents a group of inflammatory rheumatic diseases that cluster within families and possess overlapping clinical features. The pathogenesis of SpA encompasses a complex array of genetic, immunological and environmental factors. In this article, we will briefly review the genetics of PsA, and then focus on the genes that may be potentially linked either directly or indirectly to the immunopathology of the Th-17 pathway. The most consistent and dominant genetic effect of PsV and PsA is located on chromosome 6p21.3 within the major histocompatibility complex (MHC) region, which accounts for approximately one-third of the genetic contribution of PsV and PsA. To date, 36 genes have reached genomewide significance, accounting for approximately 22% of psoriasis (PsV) heritability. Prominent genes identified via GWAS include HLACw6, IL12B, IL23R, IL23A, TNIP1, TNFAIP3, LCE3B-LCE3C, TRAF3IP2, NFkBIA, FBXL19, TYK2, IFIH1, REL, and ERAP1. Genes identified in psoriatic arthritis (PsA) has largely echoed those in PsV and include HLA-B/C, HLA-B, IL-12B, IL-23R, TNIP1, TRAF3IP2, FBXL19, and REL. The lack of identified genetic susceptibility loci is largely attributed to the much smaller number of PsA patients and the greater clinical heterogeneity of PsA. Searching for different types of genetic variants such as small CNVs and/or insertions/deletions has also led to the identification of several genes with a function relative to PsV in particular including DEFB4, LCE3C_LCE3B, and IL-22 gene (exon 1). The candidate genes identified in PsV/PsA have highlighted pathways of critical importance to psoriatic disease including distinct signaling pathways comprised of barrier integrity, innate immune response and adaptive immune response, mediated primarily by Th-

* Eastern Health, Memorial University, 154 LeMarchant Rd., St. John's, Newfoundland A1C 5B8, Canada. E-mail addresses: [email protected] (D.D. O'Rielly), [email protected] (P. Rahman). 1 Tel: þ1 709 777 2416.

http://dx.doi.org/10.1016/j.berh.2014.10.010 1521-6942/© 2014 Elsevier Ltd. All rights reserved.

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17 and Th-1 signalling. While GWAS studies have yielded great insights into the genes that contribute to the pathogenesis of PsV and PsA, replication in large cohorts, fine-mapping and resequencing efforts, together with functional studies of genetic variants identified, are warranted to better understand susceptibility to and progression of these diseases. That searching solely for common variants by GWAS will identify only a fraction of the entire genetic burden of disease, a concerted effort is underway to search for highly penetrant but rare disease alleles in families with PsV and PsA, using nextgeneration sequencing and through epigenetic investigations. © 2014 Elsevier Ltd. All rights reserved.

Introduction Spondyloarthritis (SpA) represents a group of inflammatory rheumatic diseases that cluster within families, have overlapping clinical features, and share common pathogenesis, particularly with respect to the critical role of the T helper (Th)-17 axis in initiating and propagating inflammation in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). In this section, we briefly review the genetics of PsA, and then focus on the genes that may be potentially linked either directly or indirectly to the immunopathology of the Th-17 pathway. The pathogenesis of SpA encompasses a complex array of genetic, immunological, and environmental factors. Population-based studies suggest a strong genetic basis to PsA given the impressive magnitude of familial aggregation. The recurrence ratio of PsA among first-degree relatives (l1) ranges from 30 to 55, which ranks second only behind AS, and this value is considerably higher than what is estimated in psoriasis [1,2]. Additional evidence regarding the genetic basis of PsA arises from class I human leukocyte antigen (HLA) associations, non-HLA major histocompatibility complex (MHC) genes, and validated genetic associations outside the MHC region [3]. Additionally, there is a robust genetic association for psoriasis vulgaris (PsV). Much of what has been identified regarding the genetics of PsA has originated from studies in PsV, as the genetics of PsV have been more thoroughly investigated. Genetic associations in PsV are relevant to PsA as the two diseases are interrelated epidemiologically and share similar immunopathology. Almost all patients with PsA either have or will develop PsV, and approximately 30% of patients with PsV have PsA [4]. Therefore, PsA and PsV will undoubtedly share common genetic variants.

Genetic associations within the MHC region (directed genetic studies) All genetic investigations to date have revealed that the most consistent and dominant genetic effect of PsV and PsA is located on chromosome 6p21.3 within the MHC region, accounting for approximately one-third of the genetic contribution of PsV and PsA [3]. The genetic variants identified to date involve class I HLA alleles and, to a lesser extent, non-HLA genes within the MHC region. The major effect in the MHC region is located within an ~300-kb segment known as psoriasis susceptibility region 1 (PSORS1). Elegant resequencing studies have confirmed that HLA-Cw*0602 is the PSORS1 risk variant in PsV [5]. This is a reproducible finding among all type 1 PsV cohorts. Potential genotypeephenotype correlations with HLA-Cw*0602 include early age of onset, higher likelihood of familial psoriasis, guttate psoriasis, and presence of the Koebner phenomenon [6]. The presence of HLA-Cw*0602 may also lead to improvement of psoriasis during pregnancy [6]. HLA-Cw*0602 is also associated with PsA; however, the magnitude of association is lower than in PsV [7]. In fact, among PsV patients, individuals who carry the HLA-Cw*0602 allele have a delayed onset of PsA and also are less likely to develop PsA. Other HLA antigens associated with PsA include HLA-B13, HLA-B27, HLA-B38/39, HLA-B57, and HLA-DRB1*04 [7]. The most recent caseecontrol and family-based association study by Chandran et al. demonstrated that HLA-C*12/B*38, HLA-B*27, and HLA-C*06/B*57 are haplotypes (alleles) robustly associated with PsA [8].

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HLA alleles have also been associated with disease expression and prognosis in PsA. The effect sizes for these associations have been modest, thus limiting its clinical utility. Peripheral polyarthritis in PsA is associated with B38 and B39, while axial involvement is associated with HLA-B27 [9]. Dactylitis occurs more frequently in individuals carrying the HLA-B27 allele [10]. With respect to the progression of PsA, HLA-B39 alone, HLA-B27 only in the presence of HLA-DR7, and HLA-DQ3 only in the absence of HLA-DR7 and HLA-Cw*0602 are associated with a higher rate of disease progression in PsA [11]. Among PsV patients, pre-genome-wide association study (GWAS) candidate gene studies identified several HLA-B alleles and non-HLA genes (such as CDSN, HCR, and PSORS1C3), but their independence from HLA-C has not been proven [12]. In PsA, non-HLA candidates within the MHC region have produced conflicting results. The most replicated associations have been with the tumor necrosis factor (TNF)-a promoter polymorphisms (TNF-238G/A and TNF-857T) and MIC alleles, particularly trinucleotide repeat polymorphism, MICA-A9, that corresponds to MICA*002 [7,13]. A recent PsA association study confirmed the previous association of the KIR2DS gene, especially KIR2DS2, with PsA [14]. Genome-wide strategies Hypothesis-free association-based studies involve genome-wide linkage studies and GWASs. A number of genome-wide linkage studies were completed between 2005 and 2009. Linkage methods were initially used for the identification of susceptibility determinants across the entire genome. The immediate appeal of linkage studies is the ability to identify novel genes, which may not have been initially considered as potential targets. However, the genome-wide linkage studies in complex rheumatic diseases have traditionally been underpowered, and have sparse marker (microsatellite) coverage and relatively small sample sizes, and very few loci identified by linkage studies have been replicated. The most consistently replicated locus resides within the MHC region at chromosome 6p21.3 referred to as PSORS1 [5]. It is estimated that this region accounts for one-third to one-half of the genetic susceptibility to PsV. Nine other prominent regions of linkage were identified from all the genome-wide linkage scans, designated PSORS2ePSORS10 (as reviewed by Duffin et al.) [10]. These regions have not been consistently replicated but selected loci do contain potential candidate genes of interest in the pathogenesis of PsV/PsA. For instance, a region that contains a gene that regulates the production of type 1 interferon (IFN) is noted in PSORS3 (4q34); a gene that encodes S-100 proteins that are involved in chemotaxis resides within PSORS4 (1q21); the JUNB gene, which is an essential component of the AP-1 transcription factor, was identified within PSORS6 (19p13); and a gene that contains an important cytokine in PsV, interleukin 15 (IL-15), is located within PSORS9 (4q31) [10]. Only a single genome-wide linkage study has been completed in PsA, and a suggestive linkage was noted on chromosome 16q. In this Icelandic study, a significant logarithm of odds (LOD) score was only achieved, when the linkage analysis was conditioned on paternal transmission [15]. Since 2007, single-nucleotide polymorphism (SNP)-based GWASs have revolutionized the identification of genomic regions associated with complex diseases. GWASs have identified approximately 2000 robust associations with >300 complex diseases and traits [16]. The number of candidate genes identified is much greater than for linkage-based studies or candidate gene association studies. In PsV, three large GWAS studies have been published, predominantly in cohorts of European ancestry. To date, 36 genes have reached genome-wide significance among Caucasians, accounting for approximately 22% of its estimated heritability [17] (Table 1). Prominent genes identified via GWASs include HLA-Cw6, IL-12B, IL23R, IL-23A, TNF-induced protein 3 (TNFAIP3)-interacting protein 1 (TNIP1), TNFAIP3, LCE3B-LCE3C, TRAF3IP2, NFkBIA, FBXL19, TYK2, IFIH1, REL, and endoplasmic reticulum aminopeptidase 1 (ERAP1) [17]. Relatively small GWASs have also been completed in multiple PsA cohorts with two larger GWAS studies yet to be published [18]. Genes identified in PsA have largely echoed those in PsV and include HLA-B/C, HLA-B, IL-12B, IL-23R, TNIP1, TRAF3IP2, FBXL19, and REL [19e21]. The relative lack of genomewide significant genes in PsA as compared with PsV is likely attributed to the much smaller number of PsA patients who have been studied. The greater clinical heterogeneity of PsA may also contribute to the lack of genome-wide significance. The candidate genes identified in PsV/PsA have highlighted pathways of critical importance to psoriatic disease including distinct signaling pathways comprising barrier integrity, innate immune response, and adaptive immune response, mediated primarily by Th17 and Th-1 signaling.

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Table 1 Genetic associations identified in psoriasis (PsV) and psoriatic arthritis (PsA) with respect to the Th-17 pathway. Gene/Locus

Chr.

Ethnic ancestry

Psoriatic disease PsV

Th-17 Cell Differentiation IL-6 7p21 European IL-1RN 2q14.2 European IL-12b 5q31.1eq33.1 European IL-23A 12q13.3 European IL-23R 1p31.3 European TYK2 19p13.2 European STAT3 17q21.31 European SOCS1 16p13.13 European ETS1 11q23.3 European Th-17 Effector Signaling IL-17RD 3p14.3 European IL-22 12q15 Asian IL-2/IL-21 4q27 European Crosstalk with Innate Immune Response (TNF-a and NFkB) TNF-a 6p21.3 European

X X X X X X X X X

Signaling pathways affected

PsA

X X X X

X X X

X

X

X

TNIP1

5q32eq33.1

European

X

X

TNFAIP3 CARD14 REL CARM1 NFkBIA

6q23 17q25 2p13ep12 19p13.2 14q13

European European European European European

X X X X X

X

FBXL19 UBE2L3

16p11.2 22q11.21

European European

X X

X

IL-6 pathway IL-1 pathway IL-23 pathway IL-23 pathway IL-23 pathway IL-23 pathway IL-23 pathway IL-23 pathway IL-23 pathway IL-17 pathway IL-22 pathway IL-21 pathway TNF-induced NFkB-dependent gene expression TNF-induced NFkB-dependent gene expression NFkB activation NFkB activation Essential part of NFkB complex Transcriptional coactivator of NFkB Interferes with nuclear localization signals Inhibits NFkB signaling Ubiquitination of NFkB

Bold represents genetic loci common to both PsV and PsA immunopathology.

Genes altering signaling pathways involved in antigen presentation Immunopathology. Antigen presentation is a critical event in inciting SpA. Disruption of antigen presentation and alternation of CD8 T cell signaling can result in inappropriate targeting and destruction of cells, thereby contributing to SpA pathogenesis. Genetic Pathology. Variations within five genes encoding proteins crucial for antigen presentation have been identified in GWASs investigating susceptibility to PsV including HLA-B, HLA-C, ERAP1, ERAP2, and MICA [11,17,19e27]. The main function of the product of ERAP1 is to trim peptides in the endoplasmic reticulum for MHC class I presentation [28], and ERAP1 interacts with HLA-C [24,26]. ERAP2 trims peptides in the ER before their MHC class I presentation and forms heterodimers with ERAP1 [29]. Secondary analyses of recent GWASs have convincingly demonstrated the geneegene interactions of ERAP1 and HLA-Cw6 in PsV [24]. The following seven genes (RUNX3, ETS1, TNFRSF9, IRF4, MBD2, TAGAP, and B3GNT2) identified in PsV GWAS encode proteins important for T cell function and proper antigen presentation [17]. RUNX3, TNFRSF9, and MBD2 encode proteins involved in the generation of CD8 T cells [30e32], while ETS1, IRF4, TAGAP, and B3GNT2 encode proteins involved in the activation and differentiation of CD8 T cells [30,33,34]. Genes involved in innate immunity Activation of the innate immune response secondary to the disruption of barrier integrity (possibly by genetic variation) represents the initial physiological trigger, which sets in motion an inflammatory cascade initiating PsV/PsA pathogenesis. The resultant inflammatory milieu and related downstream cellular signaling tip the immune balance towards autoimmunity. IFNs and TNF-a appear to represent the predominant cytokines involved in triggering the innate immune response in PsV and PsA as

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evidenced by their release from dendritic cells in damaged skin and synovial fluid, respectively [35,36]. Interestingly, both cytokines signal via the immediate-early response transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), which represents one of the most important transcriptional regulators of the innate immune response. IFN signaling Immunopathology. IFN signaling is an important early mediator of inflammation producing proinflammatory cytokines (e.g., TNF-a and IL-1) and regulating effector cells in the innate immune response [37]. IFNs are a family of proteins consisting of three major types: type I (IFN-a, IFN-b, IFN-ε, and IFN-u), type II (IFN-g), and type III (IFN-l1, IFN-l2, and IFN-l3) [38]. Genetic Pathology. Genetic variation in this pathway may cause accumulation of proinflammatory cytokines contributing to psoriatic disease. To date, variations within eight genes encoding proteins crucial for IFN signaling have been identified in GWASs investigating susceptibility to PsV including ELMO1, TYK2, SOCS1, IFIH1, RNF114, IRF4, DDX58, and IFNLR1 [11,17,19e26]. By contrast, only a single genetic locus involved in IFN signaling, TYK2, has reached genome-wide significance in PsA [20,23]. ELMO1 is a protein-coding gene, which is essential for IFN-a induction by plasmacytoid dendritic cells [39]. TYK2 encodes a tyrosine kinase involved in the initiation of IFN-a signaling, and SOCS1 is a member of the suppressor of cytokine signaling family of proteins and interacts with TYK2 in cytokine signaling [40]. The RNA helicase encoded by IFIH1 initiates a transduction cascade that stimulates several cytokines including IFNs [41]. RNF114 encodes a protein, which regulates a positive feedback loop enhancing the production of type I IFNs [42]. IRF4, which codes for interferon regulatory factor (IRF)-4, is important in the regulation of IFNs and IFN-inducible genes. It also negatively regulates Toll-like-receptor (TLR) signaling that is central to the activation of the innate immune system [43]. DDX58 encodes for a DEAD box protein that is involved in initiating the cascade of events leading to the activation of transcription factors (IRFs and NFkB), followed by the activation of IFN genes [44]. The protein encoded by IFNLR1 belongs to the class II cytokine receptor family, which interacts with three closely related cytokines, including IL-28A, IL-28B, and IL-29 [45]. Collectively, the genetic loci revealed by GWASs support a role of IFNs in the pathogenesis of psoriatic disease. The discrepancy regarding the number of loci involved between psoriasis and PsA is a reflection of the limited number of studies for the latter. TNF-a signaling Immunopathology. TNF-a is similar to IFNs with respect to both being key effectors of innate immune responses. TNF-a induces the production of inflammatory chemokines resulting in the accumulation of proinflammatory leukocytes, including neutrophils, monocytes, and activated T cells [46]. Of relevance to PsA, TNF-a also stimulates bone loss by mobilizing osteoclast precursors from the bone marrow and by reducing bone formation by inhibiting osteoblast differentiation and function [47,48]. TNF-a binds to TNFR1 or TNFR2, which activates two separate intracellular signaling pathways leading to gene transcription through NFkB activation [49,50]. Genetic Pathology. Given that TNF-a is a key effector of innate immune responses and is tightly linked to NFkB-mediated transcription, alterations in TNF-a signaling by genetic alteration may initiate the transcription of numerous target genes contributing to psoriasis or PsA pathogenesis. Although GWASs failed to detect any association signals for TNF-a genetic variants with psoriasis or PsA, a metaanalysis, which consisted of 2159 and 2360 psoriasis and PsA patients, respectively, investigated the effect of TNF-a genetic variants on susceptibility to psoriasis and PsA [51]. The meta-analysis revealed a significant association between TNF-a-238A/G and TNF-a-857T/C polymorphism and PsA susceptibility [51]. By contrast, the variant genotypes and alleles of TNF-a-308A/G proved to be protective against PsV, whereas TNF-a-238A/G was found to have a risk association [51]. NFkB signaling Immunopathology. The NFkB complex is activated upon liberation from inhibitor of kappa B kinase (IkB), secondary to cytokine stimulation, most notably, TNF-a and IL-17. This activation leads to

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phosphorylation, ubiquitination, and finally degradation of the cytosolic IkB protein, which forms a complex with NFkB [52]. Unbound NFkB can enter the nucleus to initiate the transcription of multiple genes, which encode proteins that control inflammatory processes including proinflammatory cytokines [52]. The importance of NFkB signaling is supported by studies confirming the presence of altered NFkB activity in psoriatic disease [53,54]. Genetic Pathology. A role of the NFkB pathway in PsV and PsA is suggested by findings from GWASs. Variations within ten genes encoding proteins crucial for NFkB signaling and transcription have been identified in GWASs investigating susceptibility to PsV, including TNFAIP3, TNIP1, TYK2, REL, NFkBIA, CARD14, CARM1, NOS2, UBE2L3, and FBXL19 [11,17,19e26]. Likewise, several genetic loci involved in NFkB signaling, TNIP1, REL, FBXL19, and TYK2, have reached genome-wide significance in PsA [20,23]. TNFAIP3 encodes TNFAIP3 or Act1, and its ubiquitination in response to NFkB activation negatively regulates the subsequent NFkB activation [55]. Interestingly, Act1 is known to contribute to both skin inflammation and bone destruction [56,57]. The product of TNIP1 interacts with TNFAIP3 to inhibit TNF-induced NFkB-dependent gene expression [58]. REL genes encode a subunit of the NFkB complex that is essential for proper signaling and the product of NFkBIA interferes with nuclear localization signals by inhibiting the activity of dimeric NFkBeREL complexes [59]. CARD14 encodes a member of the family of caspase recruitment domain-containing scaffold proteins and mediates the recruitment and activation of the NFkB pathway [60]. CARM1 is a transcriptional coactivator of NFkB and functions as a promoter-specific regulator of NFkB recruitment to chromatin [61]. NFkB can induce transcription of NOS2, which encodes an inducible form of nitric oxide synthase known as an effector of the innate immune system [62]. On the other hand, UBE2L3 encodes an enzyme involved in the ubiquitination of NFkB precursor p105 [63]. The product of FBXL19 reversibly inhibits NFkB signaling, and the expression of FBXL19 is significantly elevated in psoriatic compared with normal skin [21]. Collectively, the genetic loci revealed by GWASs support a role of NFkB in the pathogenesis of psoriatic disease. Adaptive immunity: Th-17 signaling pathway The Th-17 pathway and the IL-23/IL-17 axis play a prominent role in adaptive immunity with respect to psoriatic disease [64]. Th-17 cells produce IL-17, which induces proinflammatory cytokines and angiogenic factors [65] and commits naive T cells to the Th-17 lineage creating a positive feedback loop [66]. Therefore, disruption of this signaling pathway by genetic variation can contribute to PsV/ PsA pathogenesis. Indeed, the discovery of IL-17 and the Th-17 subset has substantially changed our understanding of disease pathogenesis. In this section, we focus on the genetics involved in both Th-17 differentiation and downstream Th-17-mediated signaling (e.g., IL-17, IL-21, and IL-22). In addition to a role in adaptive immunity, the Th-17 pathway, through its intermediaries, forms a complex interplay with TNF-a and NFkB and, consequently, plays an important role in both the innate immune response and bone remodeling; the latter is of particular importance to PsA pathology. The binding of IL-23 to its receptor stimulates the degradation of IkB kinase resulting in NFkB activation [67]. Similarly, the binding of IL-17 to its receptor triggers Act1 to associate with inducible IkB kinase, IKKi [68], and binds TRAF6, which activates NFkB activator protein 1 (AP-1) or the CCAAT-enhancer-binding protein (C/EBP) cascade [69,70]. Act1 can also act independently by ubiquinating TRAF6 resulting in the activation of NFkB [71]. Therefore, both IL-23 and IL-17 influence the activation of the NFkB pathway in multiple ways. Synergistic effects likely exist between IL-17 and TNF-a, given that a combination of the two cytokines induces greater changes in gene expression than either alone [72]. This finding is consistent with a report of the effective treatment of psoriasis with a TNF-a inhibitor (i.e., etanercept) being linked to suppression of IL-17 signaling, not immediate-response TNF-a genes. [73]

Th-17 cell differentiation The current overarching understanding of the pathogenesis of both PsV and PsA with respect to the Th-17 pathway is that IL-17-promoting cytokines (e.g., transforming growth factor b (TGFb), IL-6, IL-1b, and IL-23) and their signaling pathways trigger or induce Th-17 cell differentiation culminating in a psoriatic phenotype.

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TGFb signaling Immunopathology. TGFb is a multipotent cytokine that regulates both cell growth and differentiation [74]. The active TGFb ligand binds to a heterodimeric receptor complex comprising type I and type II TGFb receptors (TGFbRI and TGFbRII), which phosphorylates downstream mediators (e.g., Smad2 and Smad3) [75]. Skin has been demonstrated to be an important target tissue of TGFb as increased TGFb1 in the epidermis and the serum has been detected in psoriatic patients [77], and the TGFb1 serum level was closely correlated with disease severity [78,79]. Genetic Pathology. TGFb1 polymorphisms have not been reported to be associated with susceptibility to PsV or PsA, but may be important for the type of disease as there appears to be a difference in TGFb1 polymorphisms between type I and type II PsV [80]. It has also been reported that TGFb1 polymorphisms significantly affect serum levels of TGFb1 in other complex diseases, but it remains unclear whether these polymorphisms correlate with PsV [81]. Additional studies in both PsV and PsA are warranted in order to clarify the role of TGFb1 in disease pathogenesis. IL-6 signaling Immunopathology. With respect to Th-17 differentiation, IL-6 appears to be involved at different key points of PsV pathogenesis, like in the differentiation of Th-17 cells from naive T cells, or in the IL23-induced skin inflammation, which cannot occur in its absence [82,83]. IL-6 signaling through signal transducer and activator of transcription 3 (STAT3) is crucial both for IL-23 receptor expression and for IL-17A and IL-17F induction [84,85]. Genetic Pathology. There have been no studies in PsA and only a couple of studies have investigated the genetics of IL-6 in the pathogenesis of PsV, which produced conflicting results [86,87]. The first study reported no significant differences in the polymorphisms of the IL-6 gene between patients with PsV and healthy controls [86]. However, a subsequent study published in 2008 revealed that the IL-6 SNP rs1800795 is associated with a lower risk of PsV [87]. Consequently, additional studies investigating the effect of IL-6 genetics on susceptibility to PsV and PsA are warranted. IL-1b signaling Immunopathology. Based on current evidence, Th-17 cell differentiation from naive T cells requires TGFb1 and IL-6, but sustained differentiation of Th-17 cells also requires IL-1b and IL-23 [88,89]. IL-1b, which is produced by activated macrophages, is involved in the inflammatory response by stimulating thymocyte proliferation, B-cell maturation and proliferation, and fibroblast growth factor activity. A role for IL-1 in PsV pathogenesis is supported by IL-1 family members being enhanced in psoriatic skin [90] and data suggesting a role for IL-1F family members in PsV. Genetic Pathology. GWASs in PsV have failed to detect an association of IL-1b gene variants [11,17,19e26]; however, a significant association of the severity of cutaneous disease with IL-1RN and nail involvement in purely cutaneous psoriasis has been reported [91]. Although there were initial reports of the IL-1 locus appearing to be a high-priority susceptibility locus in PsA [92,93], this finding was not confirmed in follow-up studies, including genome-wide analyses [19e21,94]. Further studies investigating the effect of IL-1b variants in PsV and PsA susceptibility are warranted. IL-23 signaling Immunopathology. IL-23 is a heterodimeric cytokine, composed of a p19 subunit and a p40 subunit; it binds IL-23R and IL-12Rb1, the latter being shared with IL-12 [95,96]. IL-23 promotes the expansion and survival of Th-17 cells through its receptor and signaling pathway [97]. IL-23 acts as a proinflammatory mediator and can induce the production of several proinflammatory cytokines such as IL17, TNF-a, IL-17F, IL-6, IL-21, and IL-22 [51,98e100], all of which contribute to chronic inflammatory responses in psoriatic diseases. It is now evident that IL-23 plays a crucial role in psoriasis and PsA. Serum levels of the IL-12/23 p40 subunit are significantly higher in PsA patients compared to healthy controls [101]. Monocytes from patients with PsV or PsA produce high levels of IL-23, which induces the differentiation of Th-17 cells that produce IL-17, which, in turn, stimulates keratinocyte proliferation [100]. Given the importance of IL-23R and IL-23 stimulation for the Th-17 subset, collectively, these data suggest a primary role of the Th-17 subset in psoriasis and PsA.

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Genetic Pathology. IL-23 expression is significantly increased in the skin of patients with PsV, especially in psoriatic lesions compared to biopsies of normal adjacent skin [102]. GWAS analyses have revealed that variations located within IL-12b, IL-23A, IL-23R, TYK2, STAT3, SOCS1, and ETS1 are associated with susceptibility to PsV [11,17,19e26]. While GWASs in PsA have only identified a single variation located within IL-12b [20,23], results from candidate gene studies have revealed an association with IL-23A, IL-23R, and STAT3 [18,103,104]. TYK2 encodes Tyk2, which binds directly to IL-12Rb1 and is essential for IL-23-mediated signaling and Th-17 cell differentiation. STAT3 encodes for Stat3, which is required for the differentiation of Th-17 cells [105]. Specifically, STAT3 is known to induce RAR-related orphan receptor gamma (RORg) and RORa, both of which are encoded by RORC to establish Th-17 cell differentiation [96,106,107]. Interestingly, RORgt has been argued to be the master regulator of Th-17 differentiation, a notion that supported the lineage sovereignty of Th-17 cells [53,108]. SOCS1 encodes Socs1, which regulates Th-17 differentiation by maintaining STAT3 transcriptional activity [109]. ETS1 encodes Ets1, which is a negative regulator of Th-17 differentiation [110]. These studies support a prominent role of IL-23 in the pathogenesis of both PsV and PsA. Th-17 effector signaling The differentiation of Th-17 cells set in motion downstream Th-17-mediated signaling, which mostly includes IL-17, IL-21, and IL-22. This signaling cascade results in autoimmunity, setting the stage for the development of PsV and PsA. Candidate gene studies, GWASs, and gene expression profiling evidence a genetic component in Th-17-mediated signaling. IL-17 signaling Immunopathology. IL-17 signals through IL-17RA and IL-17RC receptors to recruit the Act1 adapter, which, in turn, recruits TRAF2, TRAF5, and TRAF6 [111,112]. The major signaling pathway for IL-17 is through C/EBP transcription [113,114]. IL-17 may activate various cells such as macrophages, dendritic cells, endothelial cells, fibroblasts, chondrocytes, and osteoblasts to produce numerous products that have proinflammatory and/or destructive effects [64,115,116]. Genetic Pathology. The relevance of IL-17 in psoriatic disease is suggested by the elevation of IL-17/ IL-17R in psoriatic skin and synovial fluid from PsA patients [117e120]. Recently, significantly impaired messenger RNA (mRNA) expression levels of IL-17RB, IL-17RC, IL-17RD, and IL-17RE in lesional psoriatic skin have been reported [121]. Currently, GWASs have not identified an association of IL-17 with either PsV or PsA [11,17,19e26]. A family-based association study in Tunisian familial PsV revealed an association with IL-17RD (rs12495640), which is a member of the IL-17 receptor (IL-17R) family [122]. The significant association between IL-17RD and psoriasis combined with the aforementioned data of the significantly impaired mRNA expression levels of IL-17RD in lesional psoriatic skin (IL-17R) support the implication of IL-17 in the pathogenesis of PsV and likely PsA. However, in PsA patients of northern Italian origin, IL-17A and IL-17-RA allelic variants were not associated with disease susceptibility [123]. Additional studies are needed to fully understand the exact role of IL-17 in PsV and PsA. IL-22 signaling Immunopathology. IL-22, a newly discovered Th-17 cytokine, belongs to a family of cytokines structurally related to IL-10. This cytokine is uniquely positioned in the communication between the immune system and the epithelium, and, consequently, it is one of the most important cytokines in the pathogenesis of PsV, contributing to proliferation and differentiation of keratinocytes [124]. Genetic Pathology. Evidence indicates that IL-22 receptor (IL-22R) expression is enhanced in the epidermis of PsV compared with normal skin, with expression limited mainly to epithelial cells, including epidermal keratinocytes [125]. While the genetic association of IL-22 to PsV has not surfaced in GWASs in Caucasian populations, an IL-22 association to PsV was recently reported in the Japanese population [126]. Results for a subsequent study indicate that a genotype in the IL-22 promoter enhancing IL-22 production is preferentially enriched in PsV with onset before puberty [127]. A study investigating the contribution of copy number variations (CNVs) to PsV susceptibility in an Estonian population revealed that the IL-22 gene (exon 1) is strongly associated with early-onset PsV in an Estonian population. A protective effect for PsV was observed in patients who had lower IL-22 exon 1

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copy number while individuals with higher copy numbers are at an elevated risk of developing PsV. Interestingly, IL-22 gene copy numbers correlated also with clinical manifestations of PsV and patients with high copy numbers were more prone to the appearance of nail manifestations [124]. IL-21 signaling Immunopathology. IL-21 is a potent immunomodulatory cytokine. It functions by binding its receptor, IL-21R, which autophosphorylates JAK1 and JAK3 followed by subsequent phosphorylation of STAT1 and STAT3 and, to a lesser extent, STAT4 and STAT5 [107]. IL-21 has a key role in the differentiation of Th-17 cells, leading to increased IL-17 production and IL-23R expression [128e130]. IL-21 protein levels are increased in the lesional skin of psoriatic patients as compared with non-lesional samples taken from the same patients, and both normal and disease controls [131]. Likewise, the serum IL-21 levels in patients with psoriasis are elevated and positively correlate with PASI scores [132]. These results suggest that IL-21 may play an important role in the pathogenesis of psoriatic disease. Genetic Pathology. IL-21 gene expression is increased in the lesional skin of psoriatic patients as compared with non-lesional samples taken from the same patients, and both normal and disease controls [131]. A novel psoriatic locus was identified on chromosome 4q27, which harbors the IL-2 and IL-21 genes [19]. That GWAS reported four variants (all in strong LD) within the IL-2/IL-21 region that were associated with PsA [19]. Although there was a trend towards an association with PsV, it was not statistically significant [19]. In a subsequent study, strong evidence of association with two variants in the IL-2/IL-21 (rs6822844 and rs2069778) region was reported [133]. The findings, although requiring replication, suggest that IL-2/IL-21 may play a role in the pathogenesis of PsV and PsA. Discovery of rare genetic variants In addition to GWASs, which target only single nucleotide changes, searching for different types of genetic variants such as small CNVs and/or insertions/deletions has also led to the identification of several genes with a function relative to PsV in particular. Increased DEFB4 copy number has been associated with psoriasis, with each additional copy increasing the relative risk [134]. DEFB4 encodes for a b-defensin protein involved in epidermal differentiation and are implicated in psoriasis. In particular, the epidermal expression of DEFB4 is increased approximately 400-fold during the inflammatory response in individuals with psoriasis [135]. Furthermore, a genome-wide investigation targeting CNVs identified a significant association between a 32.2-kb deletion in LCE3C_LCE3B and increased susceptibility to psoriasis in several populations [136], a finding which was subsequently confirmed by multiple GWASs in PsV studies using LCE3 variants in LD with or tagging the aforementioned deletion [19,25]. LCE3B and LCE3C are members of the LCE gene family and are located in the epidermal differentiation complex and crucial in epidermal differentiation; their disruption is speculated to lead to abnormal differentiation and psoriatic skin lesions [136]. Furthermore, a study investigating the contribution of CNVs to PsV susceptibility in an Estonian population revealed that the IL-22 gene (exon 1) is strongly associated with early-onset PsV in an Estonian population [127]. Therefore, it appears that quantitative variation in gene dosage may also contribute to susceptibility to psoriatic disease, but further investigation in larger cohorts is needed. With rapid advancements in genetic technologies, investigation of large multiplex families is once again emerging. Large-scale parallel-sequencing studies in nine Tunisian multiplex families with generalized pustular psoriasis identified a missense mutation in the IL-36 receptor antagonist (IL36RN) that resulted in enhanced production of proinflammatory cytokines by keratinocytes [137]. A separate study identified a unique gain-of-function mutation that segregated with psoriasis using direct DNA sequencing, which altered splicing within CARD14 [138]. These studies illustrate that rare variants with large effect sizes can be identified through sequencing. Conclusion Both shared and disease-specific genes are operative in conferring susceptibility to PsV and PsA, suggesting common mechanisms of susceptibility and pathogenesis. Understanding these similarities and differences between the genetic risk factors for PsV and PsA could lead to the development of more

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effective screening strategies and therapy. While GWASs have yielded great insights into the genes that contribute to the pathogenesis of PsV and PsA, replication in large cohorts, fine mapping, and resequencing efforts, together with functional studies of genetic variants identified, are warranted to better understand susceptibility to and progression of these diseases. It is now recognized that searching solely for common variants by GWAS will, however, identify only a fraction of the entire genetic burden of disease. Consequently, a concerted effort is under way to search for highly penetrant but rare disease alleles in families with PsV and PsA, using next-generation sequencing and through epigenetic investigations. Structural variations such as CNVs should also be carefully evaluated, as these variations are not being adequately captured with current genotyping arrays. 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