Psoriasis is a common and debilitating immune-mediated skin disease with a complex genetic basis. Genetic studies have provided critical insights into the pathogenesis of disease. This article focuses on the results of genetic association studies, which provide evidence that psoriasis susceptibility genes are involved in innate and adaptive immunity and skin barrier functions. The potential for disease stratification and the development of more effective treatments with fewer side effects using genetic data are highlighted.
Key points
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Psoriasis is a common and clinically heterogeneous group of immune-mediated skin diseases that includes psoriasis vulgaris and pustular variants, amongst others. Although most research has involved psoriasis vulgaris, emerging data suggest that the different clinical phenotypes may have unique immunogenetic profiles.
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Greater than 40 regions of the genome (susceptibility loci) have been found to be associated with psoriasis using genome-wide and further targeted association studies.
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Each psoriasis susceptibility locus contains many genes; the candidate causal genes within the loci suggest a key role for adaptive and innate immunity and skin barrier functions in disease pathogenesis.
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Less than 25% of psoriasis heritability has been accounted for by genetic studies and the remaining missing heritability may in part be attributable to genetic variants of low/modest effect and epigenetic mechanisms.
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Future integration of detailed phenotype information with genetic data will enable disease stratification, with potential advances in the development of diagnostic and prognostic markers, predictors of drug responsiveness, and more efficacious, less toxic targeted therapies.
Introduction
Substantial progress has been made into identifying the genetic determinants of common immune-mediated diseases. This has highlighted biologic pathways involved in disease pathogenesis and also potential novel drug targets. Nevertheless, further advancements are required before this research is translated into the development of diagnostic and prognostic biomarkers and efficacious, targeted treatments without serious side effects. The major health and economic burden associated with these diseases may then start to decline. Psoriasis is a common, chronic, immune-mediated skin disease that affects approximately 2% of the population worldwide. It is associated with considerable psychosocial morbidity and systemic diseases, such as metabolic syndrome, cardiovascular disease, and inflammatory arthritis. There are two peak ages of onset: between 15 and 30 years, and 50 and 60 years. The most common clinical phenotype of psoriasis is psoriasis vulgaris (affecting 85%–90% of patients), characterized by erythematous, scaling plaques. Most research to date (as described in this article) has explored the early onset (before age 40) form of this disease called type 1 psoriasis. Other subtypes include type 2 psoriasis (onset after age 40), guttate psoriasis, nail psoriasis and pustular variants.
Psoriasis is a complex, multifactorial disease, with genetic and environmental factors having an important role in its etiology. A strong genetic basis for psoriasis is now well established through epidemiologic studies and heritability is estimated at 60% to 90%, which is among the highest for complex genetic diseases. Initial epidemiologic studies revealed a higher incidence of psoriasis in the relatives of patients compared with the general population. Approximately 70% of individuals with childhood psoriasis report a positive family history. Twins studies showed higher concordance rates in monozygotic twins (35%–73%) than dizygotic twins (12%–20%). Segregation analyses in large, multigenerational families show that psoriasis is likely to be a polygenic disease.
Introduction
Substantial progress has been made into identifying the genetic determinants of common immune-mediated diseases. This has highlighted biologic pathways involved in disease pathogenesis and also potential novel drug targets. Nevertheless, further advancements are required before this research is translated into the development of diagnostic and prognostic biomarkers and efficacious, targeted treatments without serious side effects. The major health and economic burden associated with these diseases may then start to decline. Psoriasis is a common, chronic, immune-mediated skin disease that affects approximately 2% of the population worldwide. It is associated with considerable psychosocial morbidity and systemic diseases, such as metabolic syndrome, cardiovascular disease, and inflammatory arthritis. There are two peak ages of onset: between 15 and 30 years, and 50 and 60 years. The most common clinical phenotype of psoriasis is psoriasis vulgaris (affecting 85%–90% of patients), characterized by erythematous, scaling plaques. Most research to date (as described in this article) has explored the early onset (before age 40) form of this disease called type 1 psoriasis. Other subtypes include type 2 psoriasis (onset after age 40), guttate psoriasis, nail psoriasis and pustular variants.
Psoriasis is a complex, multifactorial disease, with genetic and environmental factors having an important role in its etiology. A strong genetic basis for psoriasis is now well established through epidemiologic studies and heritability is estimated at 60% to 90%, which is among the highest for complex genetic diseases. Initial epidemiologic studies revealed a higher incidence of psoriasis in the relatives of patients compared with the general population. Approximately 70% of individuals with childhood psoriasis report a positive family history. Twins studies showed higher concordance rates in monozygotic twins (35%–73%) than dizygotic twins (12%–20%). Segregation analyses in large, multigenerational families show that psoriasis is likely to be a polygenic disease.
Tools for investigating the genetic basis for psoriasis; a common, complex disease
In contrast to mendelian conditions, in which mutations are rare in the population and of large effect, the multiple alleles contributing to susceptibility to complex genetic diseases, such as psoriasis, are common and individually confer modest risk. Based on this “common disease–common variant” hypothesis, numerous genome-wide linkage scans and association studies have been performed in the search for the multiple genes that predispose to psoriasis.
Linkage studies identify areas of the genome that confer disease susceptibility by tracing the cosegregation of clinical phenotypes with specific genomic regions. These identified at least nine chromosomal segments (genetic loci) that cosegregate with psoriasis (PSORS1-9); however, except for PSORS1, PSORS2, and PSORS4, the evidence for susceptibility loci found by linkage studies could not be replicated. PSORS1, a 220-kb region found on chromosome 6p21.3, was shown to confer the most risk for psoriasis. It has the largest effect size, is estimated to account for between 35% and 50% of heritability, and is the most replicated locus for psoriasis. The presence of strong linkage disequilibrium (LD) across the region has made identification of the underlying disease susceptibility allele difficult. LD is the phenomenon whereby single-nucleotide polymorphisms (SNPs) that are located in close proximity in the genome are inherited together. Distinguishing the disease/causal SNP from other statistically associated ones within the same LD block is thus challenging.
The PSORS1 region contains the candidate genes human leukocyte antigen C ( HLA-C ), coiled-coil-α-helical rod protein ( CCHCR1 ), and corneodesmosin ( CDSN ). The HLA-Cw6 allele is associated with psoriasis in many different populations, suggesting that it may be the causal psoriasis susceptibility allele within PSORS1. HLA-C encodes a class I major histocompatibility complex molecule that is expressed on antigen-presenting cells and involved in CD8 + T-cell activation (via antigen presentation), thus highlighting the importance of immune dysregulation in psoriasis pathogenesis. SNPs affecting HLA-Cw6 expression have also recently been found that are likely to contribute to psoriasis susceptibility.
The statistical power of linkage studies to discover the causative genes contributing to complex diseases is, however, limited because the risk conferred by each susceptibility locus is only small. Genome-wide association studies (GWAS) soon proved to be more powerful in the analysis of common, complex diseases, such as psoriasis. In GWAS, statistical differences in allele frequencies are found between unrelated cases and control subjects (ethnically matched) within a population, hence alleles that are associated with disease are identified. It is reliant on the careful phenotyping of sufficient numbers of cases and control subjects and the accurate typing of genetic markers (SNPs) that span the genome in each individual. The completion of human genome sequencing and the development of high-throughput genotyping platforms have enabled GWAS to be a powerful and accessible tool. No prior hypotheses regarding candidate causal genes/variants are required before completing a GWAS and the candidate genes that are subsequently identified within disease-associated intervals provide critical insights into the pathogenesis of disease. Increased power to detect associations from GWAS is gained from investigating larger sample numbers, hence promoting collaborations between large centers and meta-analyses.
GWAS provides the stimulus for further work because the lead SNP within the susceptibility interval is not necessarily the causal variant. Each locus can be refined by denser SNP arrays, such as the Immunochip. The Immunochip (Illumina Infinium) contains more than 200,000 SNPs implicated in 12 immune-mediated conditions including psoriasis. In the following section, the findings from psoriasis GWAS and the Immunochip study are reviewed.
Findings from genetic studies: insights into psoriasis pathogenesis
Greater than 40 regions of the genome have now been found to be associated with psoriasis; 26 were discovered using GWAS and a further 15 psoriasis susceptibility loci were identified in the Immunochip study ( Table 1 ). Each region spans many genes; however, specific genes have been highlighted within each locus that are the most biologically plausible candidates given the function of the encoded proteins. Using the results of these investigations, a model for psoriasis pathogenesis is now emerging that combines skin barrier function, innate immunity, and adaptive immunity.
| Gene a | Chromosome | Biologic Pathway | Protein Function |
|---|---|---|---|
| TNFRSF9 | 1 | Adaptive immunity | Costimulatory molecule involved in generation of memory T cells |
| IL-28RA | 1 | Innate immunity; IFN signaling | IL-29 receptor subunit |
| RUNX3 | 1 | Adaptive immunity; T-cell activation | Transcription factor involved in promoting Th1 and memory T-cell differentiation |
| IL23R | 1 | Adaptive immunity; IL-23/Th17 axis | IL-23 receptor subunit |
| LCE3B/LCE3C | 1 | Skin barrier function | Keratinocyte structural protein |
| REL | 2 | Innate immunity; NF-κB signaling | Transcription factor (subunit) of the NF-κB family |
| B3GNT2 | 2 | Adaptive immunity | Enzyme involved in lymphocyte function |
| IFIH1 | 2 | Innate immunity; innate antiviral signaling | RIG-like helicase; antiviral receptor |
| ERAP1 | 5 | Adaptive immunity; antigen presentation | Peptidase to trim peptides for binding to MHC I |
| IL-4 , IL-13 | 5 | Adaptive immunity; Th2 signaling | Modulation of Th2 cell response |
| TNIP1 | 5 | Innate immunity; NF-κB signaling | Regulation of NF-κB signaling |
| IL12B | 5 | Adaptive immunity, IL-23/Th17 axis | p40 subunit shared by IL-12 and IL-23 |
| EXOC2 | 6 | Innate immunity; innate antiviral signaling | Promotes the production of type I IFNs in response to intracellular DNA |
| HLA-C | 6 | Adaptive immunity; antigen presentation | MHC class I |
| TRAF3IP2 | 6 | Innate immunity; NF-κB signaling | Signaling adaptor protein |
| TNFAIP3 | 6 | Innate immunity; NF-κB signaling | TNF-α inducible zinc finger protein that inhibits NF-κB signaling |
| TAGAP | 6 | Adaptive immunity | Involved in T-cell activation |
| ELMO1 | 7 | Innate immunity | Promotes toll-like receptor mediated IFN-α production |
| DDX58 | 9 | Innate immunity; innate antiviral signaling | RIG-I antiviral receptor |
| KLF4 | 9 | Innate immunity | Transcription factor that regulates macrophage activation |
| ZCH12C | 11 | Innate immunity | Zinc finger protein that regulates macrophage activation |
| ETS1 | 11 | Adaptive immunity | Transcription factor involved in regulating CD8 + T-cell and Th17 cell differentiation |
| IL23A | 12 | Adaptive immunity; IL-23/Th17 axis | p19 subunit of IL-23 |
| NFKBIA | 14 | Innate immunity; NF-κB signaling | Inhibitor of NF-κB signaling |
| SOCS1 | 16 | Adaptive immunity | Regulation of Th17 cell differentiation |
| FBXL19 | 16 | Innate immunity; NF-κB signaling | Putative inhibitor of NF-κB signaling |
| NOS2 | 17 | Innate immunity | Catalyzes the production of nitric oxide for immune defense against pathogens |
| STAT3 , STAT5A , STAT5B | 17 | Adaptive immunity | Participates in signaling downstream of multiple cytokines (eg, IL-6, IL-10, and IL-2) |
| CARD14 | 17 | Innate immunity; NF-κB signaling | Recruitment and activation of NF-κB pathway |
| MBD2 | 18 | Adaptive immunity | Transcriptional repressor involved in generation of memory T cells |
| TYK2 | 19 | Innate immunity; IFN signaling | Tyrosine kinase associated with cytoplasmic domain of cytokine receptors |
| CARM1 | 19 | Innate immunity; NF-κB signaling | Transcriptional coactivator of NF-κB |
| RNF114 | 20 | Innate immunity; innate antiviral signaling | E3 ubiquitin ligase |
| UBE2L3 | 22 | Innate immunity; NF-κB signaling | E2-ubiquitin-conjugating enzyme involved in regulating NF-κB signaling |
a For each disease-associated genetic locus, the most likely candidate gene (based on protein function) has been specified.
Adaptive Immunity
Antigen presentation to the immune system seems to be critical to the pathogenesis of psoriasis because SNPs that are in strong LD with HLA-Cw6 alleles yield the strongest association signal in all GWAS. Early onset disease (type 1 psoriasis) and a severe clinical course are highly associated with HLA-Cw6 . Furthermore, genetic variants within endoplasmic reticulum aminopeptidase 1 ( ERAP1 ) gene are associated with psoriasis. ERAP1 codes for an enzyme that trims peptide antigens into short chains consisting of nine amino acids, which can then be loaded onto major histocompatibility complex class I molecules for presentation to immune cells at the cell surface. ERAP1 alleles have been shown to interact with HLA-Cw6 (genetic epistasis) such that ERAP1 genetic variants only confer susceptibility to psoriasis in individuals also harboring the HLA-C risk allele. This provides further support for the HLA-Cw6 allele as the causal psoriasis susceptibility allele within PSORS1.
The importance of the interleukin (IL)-23/Th17 pathway in psoriasis pathogenesis has been shown in genetic and immunologic studies. Variants in or near the genes IL12B , IL23R , and IL23A are associated with psoriasis susceptibility. IL-23 is a heterodimer that signals through the IL-23R complex and is composed of IL-23p19 and IL-12p40 subunits. The IL-12p40 subunit is shared with IL-12 and encoded by the gene IL12B . The IL23A gene codes for the IL-23p19 subunit. IL-23 promotes the survival and expansion of Th17 cells and subsequent release of cytokines, such as IL-17, IL-22, and tumor necrosis factor (TNF)-α.
GWAS have shown an association between a nonsynonymous SNP in IL23R (guanine to adenine substitution; R381Q) and protection against developing psoriasis. It is also associated with protection against ankylosing spondylitis and Crohn disease. Functional characterization of this SNP has shown that the protective variant causes impaired IL-23–induced Th17 effector cell function, with reduced IL-17A production and reduced STAT3 activation (downstream of IL23R). Hence in psoriasis, there may be aberrant IL-23 signaling and Th17 cell activity, which contribute to chronic inflammation. In support, IL12B and IL23A are overexpressed in lesional skin of psoriasis patients. TYK2 encodes a kinase that promotes IL-17 transcription via STAT3 phosphorylation and also regulates type I and II interferon (IFN) signaling. Coding variants in TYK2 have also been shown to be associated with psoriasis in GWAS and the Immunochip study.
TRAF3IP2 encodes ACT1, which is an essential signaling adaptor molecule in IL-17 signaling. ACT1 can activate nuclear factor (NF)-κB through phosphorylation of the inhibitor of kappa B kinase complex. A coding variant in TRAF3IP2 (Asp10Asn) is associated with psoriasis and psoriatic arthritis, and leads to almost complete loss of binding of ACT1 to its binding partner TRAF6. The functional consequences of this susceptibility allele have been well characterized in Act1-deficient mice, who demonstrate upregulated Th17 responses and spontaneous IL-22–dependent skin inflammation.
Finally, the role of Th2 pathway modulation in psoriasis pathogenesis has been underscored by the strong associations found in GWAS between psoriasis and genes encoding the cytokines IL-4 and IL-13.
Skin Barrier Function
Linkage studies first suggested an association between psoriasis and genes expressed during epidermal differentiation that are contained within the epidermal differentiation complex. PSORS4 is on chromosome 1q21 and contains the epidermal differentiation complex. The epidermal differentiation complex encompasses the late cornified envelope (LCE) genes, which encode stratum corneum proteins involved in epidermal terminal differentiation. A GWAS of a large Chinese cohort revealed an association between SNPs in the LCE cluster and psoriasis. Furthermore, a deletion involving LCE3B and LCE3C genes was found to be associated with psoriasis in a European cohort. The expression of LCE3 genes was almost undetectable in normal and nonlesional psoriatic skin; however, it was upregulated in lesional skin and normal skin following skin injury (eg, tape stripping).
Based on the previously mentioned studies, it has been hypothesized that minor skin injury (ie, a compromised barrier) and incomplete barrier repair caused by insufficient LCE3B/3C expression promotes antigen and proinflammatory stimuli penetration, which leads to chronic inflammation.
Innate Immunity
The role of innate immunity in psoriasis pathogenesis is being increasingly recognized. The skin is the first line of defense against pathogens because it provides a physical, biochemical (eg, antimicrobial peptides), and immunologic barrier. GWAS and the Immunochip study have identified several psoriasis susceptibility loci that contain genes involved in innate immunity.
NF-κB is a family of dimeric transcription factors involved in apoptosis and innate immune regulation. NF-κB is activated via signaling cascades triggered by toll-like receptors (TLR) and cytokines including TNF, IL-17, and IL-1. Inactive NF-κB associates with cytoplasmic inhibitor proteins of the IκB family and active dimmers translocate to the nucleus. All NF-κB proteins have a Rel homology domain that mediates DNA binding and dimerization. Previous GWAS have revealed that several components of the NF-κB signaling pathway are associated with psoriasis.
Genetic variants in or near TNIP1 and NFKBIA encoding the NF-κB regulatory proteins ABIN-1 and IκBα, respectively, have been shown to be associated with psoriasis. TNFAIP3 encodes the ubiquitin-editing enzyme A20, which regulates NF-κB activation in response to TNF and microbial products that signal through TLRs. The association between TNFAIP3 and psoriasis further underscores the potential relevance of NF-κB in the pathogenesis of psoriasis. Recently the Immunochip study and candidate gene studies have confirmed an association between CARD14 and psoriasis. CARD14 is expressed in keratinocytes and regulates NF-κB. Linkage studies using large pedigrees originally identified mutations in CARD14 as being responsible for PSORS2. Common and rare coding variants have subsequently been identified, with evidence of altered NF-κB activity.
Genetic and immunologic studies are converging to highlight the potential importance of innate antiviral immune pathways in psoriasis pathogenesis. RNF114 was identified as a psoriasis susceptibility gene and found to have a regulatory role in the signaling cascade driven by the RIG-I and MDA5 innate antiviral receptors, which are encoded by DDX58 and IFIH1 , respectively. Indeed, RIG-I and MDA5 are significantly upregulated in psoriatic lesions. RIG-I and MDA5 bind viral dsRNA and promote the release of proinflammatory and antiviral cytokines, such as IL-1, IL-6, TNF, type I IFN, and IL-29. The latter cytokine is a type III IFN that signals through the receptor encoded by IL28RA . Finally, the protein encoded by EXOC2 is thought to promote the production of type I IFN in response to intracellular DNA. RNF114 , DDX58 , IFIH1 , IL28RA , and EXOC2 are all contained within psoriasis susceptibility loci identified in GWAS and the Immunochip study. Thus, altered expression of innate antiviral genes may contribute to disease susceptibility by causing the overproduction of proinflammatory cytokines. Given that the skin provides the first line of defense against pathogens, dysregulation of this antimicrobial function may have a critical role in the pathogenesis of psoriasis.
β-Defensins are antimicrobial peptides that are also proinflammatory because they act as chemokines for immune cells, such as dendritic cells and T cells. High genomic copy number of the β-defensin gene cluster was shown to be associated with risk of psoriasis in a Dutch and German cohort. This finding was replicated in a large, independent cohort (although it showed a weaker association). The β-defensin hBD-2 is highly upregulated in lesional psoriasis skin. This may provide increased protection against infection when the skin barrier is disrupted; however, it may also contribute to an overexaggerated immune response to minor stimuli and thus an increased risk of psoriasis.
Taken together, genetic studies have provided vital mechanistic insights into psoriasis pathogenesis. The psoriasis susceptibility loci have highlighted many genes involved in skin barrier function and innate and adaptive immune responses. It has also been shown that different autoimmune diseases, such as Crohn disease and celiac disease (which are more prevalent in individuals with psoriasis), share susceptibility loci with psoriasis. In support, individuals with psoriasis have an increased risk of developing a second (odds ratio 1.6) or third (odds ratio 1.9) autoimmune disease. There may be shared pathogenic mechanisms among different autoimmune diseases, and further research into these biologic pathways may highlight common, novel drug targets.
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