There is a strong familial component to psoriatic disease as well as a complex array of genetic, immunologic, and environmental factors. The dominant genetic effect is located on chromosome 6p21.3 within the major histocompatibility complex region, accounting for one-third of genetic contribution. Genome-wide association studies (GWAS) identified additional genes, including skin barrier function, innate immune response, and adaptive immune response genes. To better understand disease susceptibility and progression requires replication in larger cohorts, fine-mapping efforts, new technologies, and functional studies of genetic variants, gene–gene interactions and gene–environmental interactions. New technologies available include next-generation sequencing, copy number variation analysis, and epigenetics.
Key points
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Despite the large number of genes identified in psoriatic disease, the genetic contribution identified by genome-wide association studies (GWAS) accounts for less than 25% of heritability.
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This “missing heritability” is attributed to inherent limitations of this technology and limits searches to common variants, neglecting rare variants.
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No clinically actionable information can be gleaned by a single variant from GWAS studies owing to the very low odds ratio for the individual variants.
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A genetic risk score combining multiple loci associated with psoriasis/psoriatic arthritis may hold more clinical promise.
Genetics of psoriatic disease
Clinicians have long recognized a strong familial component to psoriatic disease, and this observation has been substantiated in population and cohort-based studies. Epidemiologic studies suggest that psoriatic arthritis (PsA) has a higher heritability than psoriasis vulgaris (PsV). However, many of the genes identified to date are related to psoriasis, whereas genes specific to PsA remain elusive.
Initial genetic studies in psoriatic disease involved interrogation of HLA alleles, which was subsequently followed by candidate gene studies within and outside the major histocompatibility complex (MHC) region. With the emergence of genome-wide microarrays, multiple genome-wide linkage studies were performed using either large multiplex families or sibling pairs. These strategies were followed by genome-wide association studies (GWAS), which also included metaanalyses. These large, international, single nucleotide polymorphism–based studies have identified numerous additional genes reaching genome-wide significance, which can be broadly classified into those involved in maintaining skin barrier functions, innate immunity, and acquired immunity. New technologies are being used to investigate the genetic basis of psoriatic disease using next-generation sequencing, copy number variation (CNV) analysis, and epigenetics.
Major Histocompatibility Complex Associations in Psoriatic Disease
The MHC region located on the short arm of chromosome 6 continues to be the dominant susceptibility region in psoriatic disease. Recent estimates suggest that at least one-third of the entire genetic contribution of psoriasis and PsA resides within this region. The major genetic determinant of psoriasis was initially localized to ∼300 kb segment in the MHC I region, known as PSORS1 ; subsequent resequencing studies concluded that HLA-Cw6 is the PSORS1 risk variant that confers susceptibility to PsV. There is also consistent association between HLA-Cw0602 and PsA; however, the magnitude of the association with PsA is lower compared with PsV. The HLA-C*0602 allele seems to be associated with subphenotypes of PsV and PsA. In patients with PsV, HLA-C*0602 is associated with type 1 psoriasis, guttate psoriasis, Koebner phenomenon, and amelioration of psoriasis during pregnancy. Among patients with PsA, the HLA-C*0602 allele is associated with delayed onset of arthritis and there is an inverse correlation with psoriatic nail disease, as summarized elswhere.
The HLA-B*27 allele seems to be a specific genetic marker for PsA; however, its magnitude is not as strong as in ankylosing spondylitis. The prevalence of HLA-B*27 is only about 20% compared with 70% to 90% in ankylosing spondylitis. The HLA-B*27 allele is also associated with selected subphenotypes of PsA, including axial involvement, dactylitis, and greater burden of articular damage. Thus, the presence of the HLA-B*27 allele in PsA may lead to a more severe form of disease.
The 3 most consistently reported HLA-B alleles that are specific to PsA are HLA-B*38 , HLA-B*08 , and HLA-B*39 . A recent large fine-mapping study of psoriatic disease within the MHC region using an HLA-variant imputation approach, has shed new light regarding HLA associations within this region for PsV and PsA. In this elegant study, Okada and colleagues defined the 4-digit HLA allele and amino acid resolutions. This study included 9247 affected individuals (3038 PsA subjects, 3098 cutaneous psoriasis (PsC) subjects, and 3111 subjects of unknown PsA or PsC status) and 13,589 control individuals of European ancestry. They found that the HLA-B*27 allele was the most discriminative allele separating PsA from PsC. A more refined analysis revealed that the presence of glutamine in position 45 of the HLA-B antigen conferred the strongest risk for PsA. This polymorphic site is located in the binding groove of HLA-B and can influence the binding of a peptide to the HLA molecule. The PsA-specific alleles noted ( HLA-B*27 , B*39 , and B*38 ) all encode proteins that contain Glu at position 45.
Non–Major Histocompatibility Complex Candidate Genes Studies in Psoriatic Arthritis
Multiple association studies of non-MHC genes have been conducted in PsA. Most association studies reporting an initial association have not been replicated and the majority have failed to demonstrate independence from association with known HLA alleles. MICA represents the non- HLA gene within the MHC region that has received the most interest. This gene is in close proximity to the HLA-B locus and, in a Spanish cohort, the trinucleotide repeat polymorphism, MICA-A9 (which corresponds with MICA*002 ), was associated with PsA independent of HLA-Cw6 , MICB , or TNF . However, the large fine-mapping study failed to demonstrate an association between MIC alleles and PsA.
The killer-cell immunoglobulin-like receptors (KIR) do not reside in the MHC region, but interact with class I HLA antigens, and therefore are covered in this article. KIRs are encoded by a highly polygenic and polymorphic locus on chromosome 19q13.4 and located on natural killer cells. The frequency of KIR2DS2 is increased in PsA compared with unaffected controls and this association is amplified when KIR2DS2 is coupled with various HLA-C ligands. The KIR2DS2 may be specific to PsA because the association is maintained when PsA and PsV were compared (odds ratio, 1.34; 95% CI, 1.04, 1.73; P = .024).
Genome-wide Linkage Scans in Psoriasis Vulgaris and Psoriatic Arthritis
Genome-wide linkage studies are only of historical significance because no convincing susceptibility variants can be attributed reliably to the linkage peaks in psoriasis. Nine genome-wide linkage studies were completed in PsV and these efforts identified 10 loci ( PSORS1 to PSORS10 ) with the strongest and most consistent association being PSORS1 at chromosome 6p21.3, as summarized by O’Rielly and Rahman. Only 1 genome-wide linkage study was completed in PsA and this study revealed evidence for significant linkage on chromosome 16q only when conditioned on paternal transmission.
Meanwhile, GWAS have resulted in multiple new candidate genes in psoriasis and PsA. The candidate genes achieving genome-wide significance are grouped into skin barrier function genes, innate immune response genes involving nuclear factor-kappa B (NF-κB) and interferon (IFN) signaling, and adaptive immune response genes involving CD8 T-lymphocytes and T helper (Th)-17 lymphocyte signaling.
Skin Barrier Function
Psoriasis is characterized by keratinocyte hyperplasia, which may develop as a result of the effects of cytokines produced by immune cells. The potential role for epidermal keratinocytes as triggers for the initiation of psoriasis has also been proposed. CNV GWAS and functional studies have identified significant associations with DEFB genes and late cornified envelope ( LCE ) genes and an Asian GWAS study identified Connexin, all reaching genome-wide significance. β-Defensins are responsible for maintaining a chemical barrier by generating small antimicrobial peptides that possess a broad spectrum of antimicrobial activity. Each additional copy above 2 copies of DEFB4 increases the relative risk of psoriasis. The DEFB4 gene, which encodes for the hBD-2 protein, is induced dramatically in skin as a part of the inflammatory response in psoriasis and psoriatic keratinocytes are programmed to secrete large amounts of β-defensins in response to ‘Th1’ or ‘Th17’ cytokines.
LCE gene cluster encodes cornified envelope proteins that are important for epidermal cell differentiation. A genome-wide investigation targeting CNVs identified a significant association within the PSORS4 locus that encompassed both LCE3B and LCE3C genes with increased susceptibility to PsV in multiple populations. GWAS followed by targeted candidate gene studies been confirmed associations with LCE3 gene in multiple populations. A gene–gene interaction (epistasis) between LCE3C_LCE3B-del and HLA-Cw6 has also been noted.
Connexin 26 is expressed at the cell periphery of keratinocytes in psoriatic plaques and is not present in normal, unaffected skin. When keratinocytes release connexin-mediated adenosine triphosphate, this indirectly results in epidermal proliferation and differentiation resembling a characteristic response in psoriasis. Connexin 26 is encoded by GJB2 and a variant residing in this gene was identified in an Asian GWAS as a PsV susceptibility locus.
Innate Immune Response
The innate immune response, which is present from birth and not adapted or persistently amplified as a result of exposure to microorganisms, is composed of physical epithelial barriers, phagocytic leukocytes, dendritic cells, natural killer cells, and circulating plasma proteins. An important cellular regulator of the innate response is the immediate–early response transcription factor NF-κB. NF-κB accumulation triggers transcription of numerous target genes, which contributes to the pathogenesis of inflammatory disease in PsV and PsA. Genes reaching genome-wide significance in psoriasis that encode proteins crucial for NF-κB signaling and subsequent transcription include REL , TNIP1 , TNFAIP3 , NFKBIA , FBXL19 , NOS2 , CARD14 , CARM1 , TYK2 , and UBE2L3 ( Table 1 ). REL genes encode 1 of the 4 subunits comprising the NF-κB complex and belong to the family of the NF-κB (REL) transcription factor, which is essential for proper signaling. Tumor necrosis factor (TNF) α–induced protein 3-interacting protein 1 ( TNIP1 ) encodes ABIN-1, which interacts with the zinc finger protein, A20, to inhibit TNF-α–induced, NF-κB–dependent gene expression. It inhibits both transduction by transmembrane receptors, such as TNF-α–receptor, epidermal growth factor receptor, and Toll-like receptor, and nuclear receptors peroxisome proliferator activated receptor and retinoic acid receptor activity. Multiple autoimmune diseases implicated TNIP1 through GWAS, including PsV and rheumatoid arthritis. TNF-α–inducible protein 3 ( TNFAIP3 ) encodes the inducible zinc finger protein A20, a critical protein in the inhibition of NF-κB signaling. Activation of NF-κB signaling triggers ubiquitination of A20, which prevents subsequent NF-κB activation. TNFAIP3 polymorphisms are associated with susceptibility to multiple autoimmune diseases, including psoriasis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and celiac disease. A large metaanalysis of the TNFAIP3 region revealed multiple associations, with the top variant being rs582757 ( P = 6.07 × 10 −12 ). Further analysis of TNFAIP3 haplotypes revealed that the psoriasis risk haplotype is distinct from other autoimmune diseases, highlighting the complex genetic architecture of this locus. NFKBIA encodes an inhibitory protein that interferes with nuclear localization, which inactivates NF-κB dimers in the absence of inflammatory stimuli. FBXL19 is a member of the F-box family and the encoded protein is reported to bind to the transmembrane receptor interleukin (IL) 1 receptor-like 1 and regulate its ubiquitination and degradation. FBXL19 is also known to reversibly inhibit NF-kB signaling. FBXL19 expression is increased significantly in psoriatic skin, suggesting a role in its pathogenesis. NOS2 encodes an inducible form of nitric oxide synthase, which is a known effector of the innate immune system, and whose transcription may be induced by NF-κB. CARD14 encodes a member of the family of caspase recruitment domain-containing scaffold proteins and mediates recruitment and activation of the NF-κB pathway, whereas CARM1 encodes a transcriptional coactivator of NF-κB and functions as a promoter-specific regulator of NF-κB recruitment to chromatin. TYK2 encodes a tyrosine kinase involved in the initiation of IFN-α signaling and NF-κB activation. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, which is involved in the ubiquitination of the NF-κB precursor p105 which prevents NF-κB activation.
| Gene/Locus | Chr. | Ethnic Ancestry | Psoriatic Disease | |
|---|---|---|---|---|
| Psoriasis | PsA | |||
| Skin barrier function | ||||
| LCE3B / LCE3C | 1q21.3 | European | X | –– |
| DEFB4 | 8p23.1 | European | X | –– |
| KLF4 | 9q31 | European | X | –– |
| GJB2 | 13q11-q12 | Asian | X | –– |
| Innate immune response | ||||
| Interferon signaling | ||||
| IFNLR1/IL-28RA | 1p36.11 | European | X | –– |
| IFIH1 | 2q24 | European | X | –– |
| ELMO1 | 7p14.1 | European | X | –– |
| DDX58 | 9p12 | European | X | –– |
| SOCS1 | 16p13.13 | European | X | –– |
| TYK2 | 19p13.2 | European | X | X |
| RNF114 | 20q13.13 | European | X | –– |
| NF-κB signaling | ||||
| REL | 2p13-p12 | European | X | X |
| TNIP1 | 5q32-q33.1 | European | X | X |
| TNFAIP3 | 6q23 | European | X | –– |
| NFKBIA | 14q13 | European | X | –– |
| FBXL19 | 16p11.2 | European | X | X |
| NOS2 | 17q11.2-q12 | European | X | –– |
| CARD14 | 17q25 | European | X | –– |
| CARM1 | 19p13.2 | European | X | –– |
| TYK2 | 19p13.2 | European | X | X |
| UBE2L3 | 22q11.21 | European | X | –– |
Genes reaching genome-wide significance in psoriasis that encode proteins important for IFN signaling include IFNLR1/IL-28RA , IFIH1 , ELMO1 , DDX58 , SOCS1 , TYK2 , and RNF114 (see Table 1 ). IL-28 receptor, alpha subunit (IL-28RA) gene, which encodes a protein that forms a receptor complex with IL-10 receptor β (IL-10RB), can influence IFN type III signaling. IFIH1 initiates a transduction cascade that induces several cytokines, including interferons, whereas ELMO1 encodes a member of the engulfment and cell motility protein family, which is essential for Toll-like receptor-mediated IFN-α induction by plasmacytoid dendritic cells. DDX58 , which encodes the RIG-I receptor, is induced by IFN-γ and regulates the production of IFN-α and INF-γ. SOCS1 is a member of the suppressor of cytokine signaling family of proteins and inhibits signaling events downstream of INF-γ and interacts with TYK2 in cytokine signaling. RNF114 encodes an ubiquitin binding protein that enhances production of IFN-α through dysregulation of RIG-I/MDA5 signaling.
With respect to PsA, TNIP1 , REL , TYK2 , and FBXL19 have reached genome-wide significance in PsA as summarized by O’Rielly and Rahman. Collectively, these data strongly support an important role of NF-κB and IFN signaling in psoriasis and PsA pathology.
Acquired Immune Response
The conventional model underling psoriasis and PsA pathogenesis was that these conditions were autoimmune based and driven by activated T cells reacting to skin or synovial antigens presented by macrophages or dendritic cells. Indeed, an inflammatory milieu characterized by a perivascular lymphocytic infiltrate of activated T cells with signs of organ-specific migration have been documented in both the skin and joints. Traditionally, psoriasis and PsA have been considered ‘Th-1’ diseases involving differentiation of naive T cells into Th-1 cells. More recently, IL-17–producing Th-17 cells maintained via IL-23 signaling by activated dendritic cells have emerged as a critical signaling pathway contributing to psoriasis and PsA pathogenesis.
Antigen presentation
Disruption of antigen presentation by genetic variation can result in inappropriate targeting and destruction of cells, thereby contributing to psoriasis and PsA pathogenesis. Variations located within RUNX3 , TNFRSF9 , MBD2 , ETS1 , IRF4 , TAGAP , B3GNT2 , ERAP1 , and HLA-B/C , which encode proteins crucial for antigen presentation, have been identified in GWAS investigating susceptibility to psoriasis ( Table 2 ). We do not discuss the genetic contribution of HLA-B/C loci to psoriasis pathogenesis because this has been covered in a previous section. RUNX3 , TNFRSF9 , and MBD2 encode proteins involved in the generation of CD8 T cells. Similarly, ETS1 , IRF4 , TAGAP , and B3GNT2 encode proteins involved in the activation and differentiation of CD8 T cells. That ERAP1 codes for a protein that trims peptides in the endoplasmic reticulum before their MHC class I presentation, and that it interacts with HLA-C indicates that this gene is important for antigen presentation. Collectively, these genes encode proteins that are important in proper antigen presentation and may underlie psoriasis pathogenesis. With respect to PsA, only variations within HLA-B/C have been identified in GWAS (see Table 2 ).
| Gene/Locus | Chr. | Ethnic Ancestry | Psoriatic Disease | |
|---|---|---|---|---|
| Psoriasis | PsA | |||
| Antigen presentation | ||||
| RUNX3 | 1p36 | European | X | –– |
| TNFRSF9 | 1p36 | European | X | –– |
| B3GNT2 | 2p15 | European | X | –– |
| ERAP1 | 5q15 | European | X | –– |
| TAGAP | 6p25.3 | European | X | –– |
| IRF4 | 6p25-p23 | European | X | –– |
| HLA-B/C | 6p21.3 | European | X | X |
| ETS1 | 11q23.3 | European | X | –– |
| MBD2 | 18q21 | European | X | –– |
| Th-1 signaling pathway | ||||
| IL-12β | 5q31.1-q33.1 | European | X | X |
| ZC3H12C | 11q22.3 | European | X | –– |
| STAT5A/B | 17q21.31 | European | X | –– |
| TYK2 | 19p13.2 | European | X | X |
| ILF3 | 19p13.2 | European | X | –– |
| Th-17 signaling pathway | ||||
| IL-23R | 1p31.3 | European | X | X |
| IL-1RN | 2q14.2 | European | X | –– |
| IL-17RD | 3p14.3 | European | X | –– |
| IL-2/IL-21 | 4q27 | European | X | –– |
| IL-12β | 5q31.1-q33.1 | European | X | X |
| TRAF3IP2 | 6q21 | European | X | X |
| IRF4 | 6p25-p23 | European | X | –– |
| IL-6 | 7p21 | European | X | –– |
| KLF4 | 9q31 | European | X | –– |
| ETS1 | 11q23.3 | European | X | –– |
| IL-23A | 12q13.3 | European | X | X |
| IL-22 | 12q15 | Asian | X | –– |
| SOCS1 | 16p13.13 | European | X | –– |
| STAT3 | 17q21.31 | European | X | –– |
| TYK2 | 19p13.2 | European | X | X |
T helper-1 signaling pathway
The Th-1 signaling pathway was originally considered to play a prominent role in the pathogenesis of psoriasis and PsA. TNF-α, IFN-λ, IFN-α, IL-6, and IL-1β induce the secretion of IL-12 by myeloid dendritic cells resulting in differentiation of Th-1 cells. Disruption of this signaling pathway by genetic variation can result in a shift toward a Th-1 phenotype contributing to the pathogenesis of psoriasis and PsA. Variations within numerous genes that encode proteins crucial for Th-1 signaling have been identified in GWAS investigating susceptibility to psoriasis, including ZC3H12C , IL-12β , TYK2 , STAT5A , STAT5B , and ILF3 (see Table 2 ). ZC3H12C encodes a zinc-finger protein regulating macrophage activation. IL-12β is involved in IL-12 receptor activation, and TYK2 , which encodes Tyk2, binds directly to IL-12Rβ1, and is involved in IL-12–mediated signaling. STAT5A and STAT5B encode members of the STAT family of transcriptional activators and participate in signaling downstream of the IL-2 family of cytokines, including IL-2, IL-7, IL-15, and IL-21. ILF3 encodes a double-stranded RNA-binding protein and is a subunit of the nuclear factor of activated T cells, a transcription factor required for the expression in T cells of IL-2. Collectively, these genes encode proteins that play an important role in Th-1 signaling. To date, only a single genetic locus ( IL-12β ) involved in Th-1 signaling has also reached genome-wide level of significance in PsA.
T helper-17 signaling pathway
The discovery of the Th-17 signaling pathway, also known as the IL-23/IL-17 axis, has enhanced dramatically our understanding of the pathogenesis of psoriasis and PsA disease. Specifically, Th-17 cells produce IL-17, which induces proinflammatory cytokines and angiogenic factors and commits naive T cells to the Th-17 lineage representing a positive feedback mechanism. Moreover, through its intermediaries, the Th-17 pathway forms a complex interplay with TNF-α and NF-κB and, consequently, also plays an important role in the innate immune response. That IL-17 displays synergistic effects with TNF-α, and that both IL-23 and IL-17 activate the NF-κB pathway in multiple ways, is consistent with suppression of IL-17 signaling with a TNF-α inhibitor in psoriasis. Genetically driven dysfunction of IL-23 signaling may enhance Th-17 cell expansion, with consequent IL-17–mediated upregulation of cytokines, chemokines, and tissue-degrading matrix metalloproteases, culminating in an inflammatory environment. Indeed, GWAS have identified genetic variants associated with susceptibility to psoriasis and PsA (see Table 2 ), which are involved in Th-17 differentiation effector signaling.
IL-17–promoting cytokines (eg, transforming growth factor (TGF)-β, IL-6, IL-1β, and IL-23) and their signaling pathways induce Th-17 cell differentiation culminating in a psoriatic phenotype. With the exception of IL-23, all other cytokines are covered briefly in this review. Although TGF-β1 is increased in the epidermis and the serum of psoriatic patients and TGF-β1 serum level correlates closely with disease severity, presently TGF-β1 polymorphisms have not been reported to be associated with susceptibility to psoriasis or PsA. IL-6 is involved in the differentiation of Th-17 cells and in the IL-23–induced skin inflammation. IL-6 signaling through STAT3 is required for both IL-23 receptor expression and for IL-17A and IL-17F induction. Unfortunately, there have been no studies in PsA; however, the IL-6 single nucleotide polymorphism rs1800795 was associated with a lower risk of PsV. Sustained differentiation of Th-17 cells requires IL-1β and IL-23. A role for IL-1 in PsV pathogenesis is supported by IL-1 family members being enhanced in psoriatic skin. Although GWAS studies in psoriasis failed to detect an association with IL-1β , IL-1RN was associated significantly with cutaneous disease severity and nail involvement in purely cutaneous psoriasis. Although the IL-1 locus was initially considered a PsA susceptibility locus, this finding was not confirmed in follow-up studies.
IL-23 is a heterodimeric cytokine that binds IL-23R and IL-12Rβ1, promotes the expansion and survival of Th-17 cells, and acts as a proinflammatory mediator. That IL-23 plays a prominent role in psoriasis and PsA is supported by increased serum levels and skin expression of IL-23 in patients compared with healthy controls and monocytes producing higher levels of IL-23 in patients with psoriasis or PsA. GWAS analysis has revealed that variations located within IL-12β , IL-23A , IL-23R , TYK2 , STAT3 , SOCS1 , and ETS1 are associated with psoriasis susceptibility (see Table 2 ). Whereas IL-12β , IL-23A , and IL-23R are involved in IL-23 receptor activation, TYK2 , STAT3 , SOCS1 , and ETS1 are involved with downstream signaling. TYK2 encodes Tyk2, which binds directly to IL-12Rβ1 and is essential for IL-23–mediated signaling and Th-17 cell differentiation. STAT3 and SOCS1 encode for Stat3 and Socs1, respectively, and are required for the differentiation of Th-17 cells. ETS1 encodes Ets1, which is a negative regulator of Th-17 differentiation.
Th-17 effector signaling (eg, IL-17, IL-21, and IL-22) produces autoimmunity, setting the stage for the development of psoriatic disease, and candidate gene studies, GWAS, and gene expression profiling evidence a genetic component in Th-17–mediated signaling. With the exception of IL-17, other cytokines are covered briefly in this review. IL-17 binds to IL-17RA and IL-17RC receptors and activates macrophages, dendritic cells, endothelial cells, fibroblasts, chondrocytes, and osteoblasts culminating in a proinflammatory, destructive environment. The relevance of the IL-17 in psoriatic disease is supported by the elevation of IL-17/IL-17R in psoriatic skin and synovial fluid from PsA patients. GWAS have revealed that variations located within TRAF3IP2 , KLF4 , and IRF2 are associated with psoriasis susceptibility (see Table 2 ). TRAF3 interacting protein 2 (TRAF3IP2) is required for Th-17–mediated inflammatory responses, and the TRAF3IP2 variant associated with PsA (rs33980500) nearly abolished the interaction with TRAF6. KLF4 binds to the IL-17A promoter and positively regulates its expression. Similarly, IRF4 encodes a transcription factor that regulates IL-17A promoter activity. Although GWAS have not identified an association of IL-17 with either psoriasis or PsA, a family-based association study in Tunisian familial PsV revealed an association between IL-17RD (rs12495640), which is a member of the IL-17 receptor (IL-17R) family. However, in PsA patients of northern Italian origin, IL-17A and IL17-RA allelic variants were not associated with disease susceptibility.
IL-22, a newly discovered Th-17 cytokine, contributes to proliferation and differentiation of keratinocytes, which is supported by enhanced IL-22 receptor ( IL-22R ) expression in the epidermis of psoriatic compared with normal skin. Although an association was not detected in Caucasian GWAS, an IL-22 association with psoriasis was identified in a Japanese population. IL-22 gene copy number correlated with clinical manifestations of psoriasis with high copy numbers being more prone to the appearance of nail manifestations. IL-21 binds to IL-21R, which activates the JAK-STAT signaling pathway and increases IL-17 production and IL-23R expression. IL-21 gene and protein expression is increased in lesional skin of psoriatic patients compared with nonlesional samples, and serum IL-21 levels in patients with psoriasis are increased and positively correlate with Psoriasis Area and Severity Index scores. Although there was a trend toward an association of within the IL-2/IL-21 region in psoriasis GWAS, strong evidence of association with 2 variants in the IL-2/IL-21 (rs6822844 and rs2069778) region was reported in a subsequent study.
In PsA, only 2 genetic loci (ie, IL-12B , TRAF3IP2 ) involved in Th-17 signaling have reached a genome-wide level of significance. However, results from candidate gene studies have revealed an association of IL-23A , IL-23R , and STAT3 . A prominent role of Th-17 signaling in the pathogenesis of PsA is supported by increased Th-17 cells in peripheral blood of PsA patients, which correlated with disease activity, and IL-17 and IL-23 being involved in osteoclastogenesis and bone erosion in PsA joints. Moreover, anti–IL-17 and anti–TNF-α agents suppress IL-23–induced osteoclastogenesis, and treatment with human IL-12/23 p40 monoclonal antibody is able to reduce the signs and symptoms of joint inflammation in PsA. The lack of identified genetic susceptibility loci involved in the adaptive immune response is attributed largely to the much smaller number of PsA patients interrogated with genome-wide scans and the greater degree of clinical heterogeneity observed with PsA compared with psoriasis.
Genetics of psoriatic disease
Clinicians have long recognized a strong familial component to psoriatic disease, and this observation has been substantiated in population and cohort-based studies. Epidemiologic studies suggest that psoriatic arthritis (PsA) has a higher heritability than psoriasis vulgaris (PsV). However, many of the genes identified to date are related to psoriasis, whereas genes specific to PsA remain elusive.
Initial genetic studies in psoriatic disease involved interrogation of HLA alleles, which was subsequently followed by candidate gene studies within and outside the major histocompatibility complex (MHC) region. With the emergence of genome-wide microarrays, multiple genome-wide linkage studies were performed using either large multiplex families or sibling pairs. These strategies were followed by genome-wide association studies (GWAS), which also included metaanalyses. These large, international, single nucleotide polymorphism–based studies have identified numerous additional genes reaching genome-wide significance, which can be broadly classified into those involved in maintaining skin barrier functions, innate immunity, and acquired immunity. New technologies are being used to investigate the genetic basis of psoriatic disease using next-generation sequencing, copy number variation (CNV) analysis, and epigenetics.
Major Histocompatibility Complex Associations in Psoriatic Disease
The MHC region located on the short arm of chromosome 6 continues to be the dominant susceptibility region in psoriatic disease. Recent estimates suggest that at least one-third of the entire genetic contribution of psoriasis and PsA resides within this region. The major genetic determinant of psoriasis was initially localized to ∼300 kb segment in the MHC I region, known as PSORS1 ; subsequent resequencing studies concluded that HLA-Cw6 is the PSORS1 risk variant that confers susceptibility to PsV. There is also consistent association between HLA-Cw0602 and PsA; however, the magnitude of the association with PsA is lower compared with PsV. The HLA-C*0602 allele seems to be associated with subphenotypes of PsV and PsA. In patients with PsV, HLA-C*0602 is associated with type 1 psoriasis, guttate psoriasis, Koebner phenomenon, and amelioration of psoriasis during pregnancy. Among patients with PsA, the HLA-C*0602 allele is associated with delayed onset of arthritis and there is an inverse correlation with psoriatic nail disease, as summarized elswhere.
The HLA-B*27 allele seems to be a specific genetic marker for PsA; however, its magnitude is not as strong as in ankylosing spondylitis. The prevalence of HLA-B*27 is only about 20% compared with 70% to 90% in ankylosing spondylitis. The HLA-B*27 allele is also associated with selected subphenotypes of PsA, including axial involvement, dactylitis, and greater burden of articular damage. Thus, the presence of the HLA-B*27 allele in PsA may lead to a more severe form of disease.
The 3 most consistently reported HLA-B alleles that are specific to PsA are HLA-B*38 , HLA-B*08 , and HLA-B*39 . A recent large fine-mapping study of psoriatic disease within the MHC region using an HLA-variant imputation approach, has shed new light regarding HLA associations within this region for PsV and PsA. In this elegant study, Okada and colleagues defined the 4-digit HLA allele and amino acid resolutions. This study included 9247 affected individuals (3038 PsA subjects, 3098 cutaneous psoriasis (PsC) subjects, and 3111 subjects of unknown PsA or PsC status) and 13,589 control individuals of European ancestry. They found that the HLA-B*27 allele was the most discriminative allele separating PsA from PsC. A more refined analysis revealed that the presence of glutamine in position 45 of the HLA-B antigen conferred the strongest risk for PsA. This polymorphic site is located in the binding groove of HLA-B and can influence the binding of a peptide to the HLA molecule. The PsA-specific alleles noted ( HLA-B*27 , B*39 , and B*38 ) all encode proteins that contain Glu at position 45.
Non–Major Histocompatibility Complex Candidate Genes Studies in Psoriatic Arthritis
Multiple association studies of non-MHC genes have been conducted in PsA. Most association studies reporting an initial association have not been replicated and the majority have failed to demonstrate independence from association with known HLA alleles. MICA represents the non- HLA gene within the MHC region that has received the most interest. This gene is in close proximity to the HLA-B locus and, in a Spanish cohort, the trinucleotide repeat polymorphism, MICA-A9 (which corresponds with MICA*002 ), was associated with PsA independent of HLA-Cw6 , MICB , or TNF . However, the large fine-mapping study failed to demonstrate an association between MIC alleles and PsA.
The killer-cell immunoglobulin-like receptors (KIR) do not reside in the MHC region, but interact with class I HLA antigens, and therefore are covered in this article. KIRs are encoded by a highly polygenic and polymorphic locus on chromosome 19q13.4 and located on natural killer cells. The frequency of KIR2DS2 is increased in PsA compared with unaffected controls and this association is amplified when KIR2DS2 is coupled with various HLA-C ligands. The KIR2DS2 may be specific to PsA because the association is maintained when PsA and PsV were compared (odds ratio, 1.34; 95% CI, 1.04, 1.73; P = .024).
Genome-wide Linkage Scans in Psoriasis Vulgaris and Psoriatic Arthritis
Genome-wide linkage studies are only of historical significance because no convincing susceptibility variants can be attributed reliably to the linkage peaks in psoriasis. Nine genome-wide linkage studies were completed in PsV and these efforts identified 10 loci ( PSORS1 to PSORS10 ) with the strongest and most consistent association being PSORS1 at chromosome 6p21.3, as summarized by O’Rielly and Rahman. Only 1 genome-wide linkage study was completed in PsA and this study revealed evidence for significant linkage on chromosome 16q only when conditioned on paternal transmission.
Meanwhile, GWAS have resulted in multiple new candidate genes in psoriasis and PsA. The candidate genes achieving genome-wide significance are grouped into skin barrier function genes, innate immune response genes involving nuclear factor-kappa B (NF-κB) and interferon (IFN) signaling, and adaptive immune response genes involving CD8 T-lymphocytes and T helper (Th)-17 lymphocyte signaling.
Skin Barrier Function
Psoriasis is characterized by keratinocyte hyperplasia, which may develop as a result of the effects of cytokines produced by immune cells. The potential role for epidermal keratinocytes as triggers for the initiation of psoriasis has also been proposed. CNV GWAS and functional studies have identified significant associations with DEFB genes and late cornified envelope ( LCE ) genes and an Asian GWAS study identified Connexin, all reaching genome-wide significance. β-Defensins are responsible for maintaining a chemical barrier by generating small antimicrobial peptides that possess a broad spectrum of antimicrobial activity. Each additional copy above 2 copies of DEFB4 increases the relative risk of psoriasis. The DEFB4 gene, which encodes for the hBD-2 protein, is induced dramatically in skin as a part of the inflammatory response in psoriasis and psoriatic keratinocytes are programmed to secrete large amounts of β-defensins in response to ‘Th1’ or ‘Th17’ cytokines.
LCE gene cluster encodes cornified envelope proteins that are important for epidermal cell differentiation. A genome-wide investigation targeting CNVs identified a significant association within the PSORS4 locus that encompassed both LCE3B and LCE3C genes with increased susceptibility to PsV in multiple populations. GWAS followed by targeted candidate gene studies been confirmed associations with LCE3 gene in multiple populations. A gene–gene interaction (epistasis) between LCE3C_LCE3B-del and HLA-Cw6 has also been noted.
Connexin 26 is expressed at the cell periphery of keratinocytes in psoriatic plaques and is not present in normal, unaffected skin. When keratinocytes release connexin-mediated adenosine triphosphate, this indirectly results in epidermal proliferation and differentiation resembling a characteristic response in psoriasis. Connexin 26 is encoded by GJB2 and a variant residing in this gene was identified in an Asian GWAS as a PsV susceptibility locus.
Innate Immune Response
The innate immune response, which is present from birth and not adapted or persistently amplified as a result of exposure to microorganisms, is composed of physical epithelial barriers, phagocytic leukocytes, dendritic cells, natural killer cells, and circulating plasma proteins. An important cellular regulator of the innate response is the immediate–early response transcription factor NF-κB. NF-κB accumulation triggers transcription of numerous target genes, which contributes to the pathogenesis of inflammatory disease in PsV and PsA. Genes reaching genome-wide significance in psoriasis that encode proteins crucial for NF-κB signaling and subsequent transcription include REL , TNIP1 , TNFAIP3 , NFKBIA , FBXL19 , NOS2 , CARD14 , CARM1 , TYK2 , and UBE2L3 ( Table 1 ). REL genes encode 1 of the 4 subunits comprising the NF-κB complex and belong to the family of the NF-κB (REL) transcription factor, which is essential for proper signaling. Tumor necrosis factor (TNF) α–induced protein 3-interacting protein 1 ( TNIP1 ) encodes ABIN-1, which interacts with the zinc finger protein, A20, to inhibit TNF-α–induced, NF-κB–dependent gene expression. It inhibits both transduction by transmembrane receptors, such as TNF-α–receptor, epidermal growth factor receptor, and Toll-like receptor, and nuclear receptors peroxisome proliferator activated receptor and retinoic acid receptor activity. Multiple autoimmune diseases implicated TNIP1 through GWAS, including PsV and rheumatoid arthritis. TNF-α–inducible protein 3 ( TNFAIP3 ) encodes the inducible zinc finger protein A20, a critical protein in the inhibition of NF-κB signaling. Activation of NF-κB signaling triggers ubiquitination of A20, which prevents subsequent NF-κB activation. TNFAIP3 polymorphisms are associated with susceptibility to multiple autoimmune diseases, including psoriasis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and celiac disease. A large metaanalysis of the TNFAIP3 region revealed multiple associations, with the top variant being rs582757 ( P = 6.07 × 10 −12 ). Further analysis of TNFAIP3 haplotypes revealed that the psoriasis risk haplotype is distinct from other autoimmune diseases, highlighting the complex genetic architecture of this locus. NFKBIA encodes an inhibitory protein that interferes with nuclear localization, which inactivates NF-κB dimers in the absence of inflammatory stimuli. FBXL19 is a member of the F-box family and the encoded protein is reported to bind to the transmembrane receptor interleukin (IL) 1 receptor-like 1 and regulate its ubiquitination and degradation. FBXL19 is also known to reversibly inhibit NF-kB signaling. FBXL19 expression is increased significantly in psoriatic skin, suggesting a role in its pathogenesis. NOS2 encodes an inducible form of nitric oxide synthase, which is a known effector of the innate immune system, and whose transcription may be induced by NF-κB. CARD14 encodes a member of the family of caspase recruitment domain-containing scaffold proteins and mediates recruitment and activation of the NF-κB pathway, whereas CARM1 encodes a transcriptional coactivator of NF-κB and functions as a promoter-specific regulator of NF-κB recruitment to chromatin. TYK2 encodes a tyrosine kinase involved in the initiation of IFN-α signaling and NF-κB activation. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, which is involved in the ubiquitination of the NF-κB precursor p105 which prevents NF-κB activation.
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Natural History, Prognosis, and Socioeconomic Aspects of Psoriatic Arthritis
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