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The immunological and genetic aspects in psoriasis
Applied Informatics volume 1, Article number: 3 (2014)
Psoriasis is a chronic and immune-mediated inflammatory skin disorder associated with complex genetic susceptibility. Studies focused on the immunological mechanism have revealed innate and adaptive immune activation in psoriatic lesions, including large numbers of immune cells activated to produce many cytokines, chemokines, and other inflammatory molecules. Knowledge on the genetic basis of psoriasis highlights genetic susceptibility factors that play a crucial role in regulation of immunity, epidermal proliferation, and skin barrier formation. Genetic susceptibility factors affecting both the immune system and epidermis could predispose to disease. Herein, we review the current knowledge on the role of genetic and immunological factors in the development of psoriasis.
Psoriasis (MIM *177900) is a common, chronic, and immunologically mediated inflammatory skin disease that affects individuals at rates varying from 0.5% to 4.6% across diverse ethnic populations (Lebwohl ). Symptoms typically develop in early adulthood, between the age of 15 and 25 years old (Henseler and Christophers ), but individuals of all ages can be affected. The disease has certain distinct but overlapping clinical phenotypes, including psoriasis vulgaris, which appears in approximately 90% of all patients (Griffiths and Barker ), and at least 10% to 30% of patients develop arthritis (Nickoloff and Nestle ; Ibrahim et al. ). Although psoriasis is rarely life threatening, its morbidity and associated comorbidities have a severe negative impact on the quality of life of the patients and also confer a certain socioeconomic burden. Over the past few decades, substantial researches on the pathogenesis of psoriasis have been a focus in the field of cutaneous disease. However, the mechanism of psoriasis pathogenesis likely involving the complex interplay among genetic, immunological, and environmental risk factors (Nestle et al. ) has not been fully elucidated.
The concordance of monozygotic twins both suffering from psoriasis has been reported to approximately 70%, and the sibling recurrence risk is estimated to range between 4 and 11 (Bhalerao and Bowcock ). Through a conventional family-associated on genetic linkage approach, psoriasis-associated chromosomal regions have been identified. A major genetic determinant of psoriasis, designated psoriasis susceptibility 1 (PSORS1), resides in the major histocompatibility complex (MHC) on chromosome 6p21, tightly linked to HLA-Cw6, which is as the most frequently detected allele in psoriasis (Veal et al. ; Nair et al. ). More recently, with the development of high-throughput genotyping platforms and a comprehensive map of human haplotypes, genome-wide association studies (GWAS) have evolved into a powerful tool for investigating the genetic architecture of human complex diseases (Manolio et al. ). Taking advantage of GWAS, researchers have revealed many novel and/or confirmed previous genetic loci associated with disease, and ongoing studies are exploring additional genetic factors for associated with psoriasis.
The cellular features of psoriasis are epidermal hyperplasia and altered keratinocyte differentiation, but substantial evidence implicates both innate and acquired immunity in the disease pathogenesis (Gaspari ). The disease state is triggered by an activated cellular immune system, marked infiltration of T cells, dendritic cells (DCs), and inflammatory cytokines in psoriatic skin lesions (Bowcock and Krueger ). As in other immune-mediated diseases, such as rheumatoid arthritis (RA), Crohn's disease (CD), multiple sclerosis (MS), and juvenile-onset diabetes, psoriasis is regarded as a T cell-mediated autoimmune disease (Lowes et al. ). Therefore, it fits the definition of an autoimmune disease (Davidson and Diamond ). Recent progress in the understanding of both the immunological and genetic basis of the disease has provided a deep insight into the pathogenesis. In this review, we detail the recent advances in the understanding of psoriasis pathogenesis, including the information regarding immunological factors, genetic aspects, and susceptibility genes shared with other autoimmune or inflammatory diseases.
Cells and molecules of immunity
Psoriasis is characterized by hyper-proliferation and aberrant differentiation of keratinocytes (KCs), vascular abnormalities, and inflammatory infiltration. The cell types in psoriatic plaques are involved in wound repair and/or are composed of the antigen-presenting cells (APCs), including T lymphocytes cells, KCs, DCs, Langerhans cells (LCs), and macrophages. The cellular innate and adaptive immune responses, especially the activation of T cells, play a dominant pathogenic role in psoriasis (Krueger ; Cai et al. ). Evidence for the central role of T lymphocytes has been found in animal models of psoriasis (Boehncke and Schon ), successful treatment of psoriasis patients with cyclosporine A to inhibit T cell proliferation and cytokine production (Mueller and Herrmann ) and specifically recruited T cell clones that permanently involve the psoriatic inflammation (Vollmer et al. ). A dense infiltration is composed of clusters of CD4+T cells and antigen-presenting DCs in the dermis, while CD8+T cells and neutrophils are predominant in the epidermis of psoriatic lesions (Lowes et al. ). The expression of activation markers by both CD8+T and CD4+T cells has been observed in psoriatic lesions, and most of the T cells can also express the memory cell antigens (Liu et al. ). Once the psoriatic plaques appear after T cell infiltration as the activated memory-effector T cells, cytokines, such as interleukin (IL)-2, tumor necrosis factor-α (TNF-α), and interferon γ (IFN-γ) could be generated, which stimulate an inflammatory response and change the characteristic of psoriasis (Austin et al. ; Friedrich et al. ). An interrelation exists in that, CD4+T cells may provide critical inductive and helper signals, while CD8+T cells are likely to be the principal effector agents in the pathogenesis of psoriasis (Gudjonsson et al. ). Thus, in the epidermal compartment of psoriatic lesions, CD8+T cells could be activated and proliferated after CD4+T cells interact with antigen-presenting cells.
The changes in keratinocyte activation and proliferation that cause them to mature too rapidly result in psoriasis. Keratinocytes in psoriatic lesions produce an array of immune response-related proteins, such as the S100 proteins and intercellular adhesion molecule 1 (ICAM-1), CD40, and HLA-DR, which attract leukocytes. The link is that a positive feedback leads leukocytes to upregulate the S100 proteins (Bowcock and Krueger ).Upon activation, KCs express a plethora of cytokines, chemokines, and accessory molecules, transmitting both positive and negative signals to immune cells (Albanesi et al. ). KCs also produce endothelial cell mitogens such as VEGF and PDGF, leading to angiogenesis (Costa et al. ).
DCs are professional APCs involved in the regulation of the balance between immunity and immunological tolerance. Cytokine profile studies have shown that dermal DCs obtained from psoriatic lesions mediated a T cell response with high levels of IL-2 and IFN-γ (Nestle et al. ). Plasmacytoid DCs (PDCs) have been identified in the psoriatic skin and in uninvolved, healthy-looking psoriatic skin and were shown to be the principal IFN-α-producing cells in early and developing psoriasis (Nestle et al. ). Myeloid DCs, which are activated by PDCs and keratinocyte-derived cytokines, are also accumulated in the psoriatic tissues (Zaba et al. ) and are believed to be required for sustaining and amplifying the T cell inflammatory reaction (Chu et al. ). Studies have shown that DCs may be the primary cell type that drives T-helper 17 (Th17) differentiation in psoriasis through the production of IL-6 and IL-23 (Chu et al. ). The crucial link between DCs and the IL-23/Th17 axis has been further strengthening the suggestion that DCs obtained from psoriatic lesions could activate T cells to produce both IL-17 and IFN-γ (Zaba et al. ).
LCs reside in the basal and suprabasal layers of the skin and are closely associated and interact with KCs through E-cadherin (Tang et al. ). A role for LCs has been indicated in the pathogenesis of psoriasis (Cumberbatch et al. ), inducing the generation of distinct IL-22-producing Th22 cells infiltrating into the skin (Fujita et al. ). Macrophages can contribute to both epithelial-based and T cell-mediated pathways of inflammation in psoriasis (Clark and Kupper ). Macrophages interact with KCs and secrete a variety of pro-inflammatory cytokines, such as TNF-α, IFN-α/β, IL-1β, IL-6, IL-12, IL-10, and IL-18 cytokines, under various conditions (Wang et al. [2009a]). Previous researches have suggested that the maintenance of psoriasiform skin inflammation critically depends on efficient recruitment and activation of macrophages with a sufficient release of TNF-α (Wang et al. ). As mentioned above, the cellular features of psoriasis are epidermal hyperplasia and altered keratinocyte differentiation, but mounting evidences have implicated both innate and acquired immunity in the disease progression of the disease (Nestle et al. ).
Several cytokines and chemokines, which induced keratinocyte proliferation, are strongly expressed in the psoriatic skin. It has been well established by many experimental studies that psoriatic inflammation mediated by T-helper 1 (Th1) cells (Uyemura et al. ; Schlaak et al. ). Characterization of cells and cytokines involved in the initiation and maintenance of psoriasis showed elevated levels of IFN-γ, TNF-α, and IL-12, but not of IL-4, IL-5, or IL-10, at both the mRNA and protein levels (Nestle et al. ; Schlaak et al. ; Austin et al. ). Th17 cells, a newly appreciated T cell subset that produce IL-17 (Miossec et al. ) and IL-22 (Liang et al. ), have been implicated in psoriasis. As a potent pro-inflammatory cytokine, IL-17 may stimulate keratinocytes to produce neutrophil-attracting CXC chemokines (Nograles et al. ), as well as CCL20, which draws CCR6+ cells into sites of inflammation (Harper et al. ). A mixed Th1 and Th17 inflammatory environment is found in the affected skin during the disease process (Lowes et al. ). IL-23, which is composed of two subunits, a unique p19 subunit and a p40 subunit shared with IL-12 (Lee et al. ), represents a cytokine pathway that is differentially increased in psoriatic lesions and is important in Th17 cells. IL-23 is overproduced by DCs (Lee et al. ) and stimulates Th17 cells within the dermis to make cytokines in psoriatic lesions. Recent studies have demonstrated that the IL-23/Th17 cell axis plays an important role in the pathogenesis of psoriasis and presents a potential therapeutic target (Di Cesare et al. ; Nakajima ). In addition to IL-23 and IL-17, IL-22 has also been reported to induce cutaneous inflammation in an experimental murine model of psoriasis and has also been shown to induce in vitro an inflammatory-like phenotype in vitro (Van Belle et al. ). IL-22 is a member of the IL-10 cytokine family, which is primarily secreted by Th17 cells (Trifari et al. ). IL-22 is remarkably over-expressed in psoriasis, most likely as a result of upregulated the levels of IL-23 and IL-6 (Boniface et al. ; Zheng et al. ). TNF-α has been identified as a promising target molecule, with the expression of TNF-α and its receptors enhanced in psoriasis (Ettehadi et al. ). The efficacy of TNF-α antagonists in the treatment of psoriasis suggests a central role of this factor in psoriatic plaque formation (Tobin and Kirby ).
In addition to T cell-derived cytokines, numerous antigen-presenting cells infiltrate the psoriatic skin and produce inflammatory cytokines. A variety of chemokines and chemokine receptors are present in psoriatic plaques. The percentages of peripheral blood CD8+T cells expressing CXCR6 are higher in psoriasis patients than in healthy individuals, and CXCL16-CXCR6 interactions mediate the homing of CD8+T cells to psoriatic lesion (Gunther et al. ). In immune-pathogenesis of psoriasis, including TARC (CCL17), MIG (CXCL9), IP10 (CXCL10), MDC (CCL22), and RANTES (CCL5), as well as CXCR2, CXCR3, CCR4, CCL27-CCR10, MIP3α (CCL20), MIP3β (CCL19), and CCR6, all involved in the inflammatory response of psoriasis (Nickoloff and Nestle ). Once chemokines bind to their respective receptors, they activate the cells to release of cytokines and growth factors to form a thick, erythematous scaly plaque.
Psoriasis is a representative inflammatory skin disease, which is mediated through a cytokine network. The activated DCs and T cells are central in its pathogenesis, creating a ‘Type 1’ inflammatory pathway, which links the activation of multiple inflammatory responses, such as the release of IFN-γ, IL-23, and IL-12 into the lesions (Lew et al. ). This model is conceptually useful, but it accounts for only a small fraction of the pathogenesis and cannot explain the total inflammatory character of psoriatic lesions.
Previous studies have shown that the activity of the p38 mitogen-activated protein kinases (MAPKs) is increased in the psoriatic skin, supporting the potential role of these kinases in the pathogenesis of psoriasis (Funding et al. ). The mitogen- and stress- activated protein kinases 1(MSK1) are found to be involved in the phosphorylation of cyclic adenosine monophosphate response element-binding (CREB) protein in keratinocytes and regulate the expression of the pro-inflammatory cytokines IL-6, IL-8, and TNF-α (Funding et al. ). Evidence shows that MAPK inhibitors are effective anti-inflammatory drugs that reduce the synthesis of inflammation mediators at multiple levels and block pro-inflammatory cytokine signaling (Kaminska and Swiatek-Machado ). It has therefore been confirmed that the pathway of the p38 MAPK/MSK1 signaling pathway may play a potential role in psoriasis by producing pro-inflammatory cytokines (Arthur and Darragh ).
Clearly, transcription factors, such as signal transducer and activator of transcription 1 and 3 (STAT1 and STAT3) and nuclear factor-κB (NF-κB), are activated in psoriasis. Research on the transcriptional regulatory network for psoriasis shows that E2F transcription factor 1 (E2F1), jun proto-oncogene (JUN), NF-κB 1, STAT1, STAT3, and SP3 are pivotal in the transcriptome network involved in the mechanism of psoriasis (Lu et al. ). NF-κB is a key regulatory element in inflammatory pathways, in cellular proliferation and differentiation, and in apoptosis as well as a crucial mediator in psoriasis (Goldminz et al. ). In a mouse model of psoriasis, NF-κB signaling is essential for the pathogenesis and is strongly activated in psoriatic lesions (Wang et al. [2009b]). Compared to the non-psoriatic skin, the samples of the psoriatic skin demonstrate elevated levels of activated, phosphorylated NF-κB (Lizzul et al. ). It is targeted by numerous effector cells, including keratinocytes, Th17, and DCs, which respond to extracellular stimuli consisting of TNF-α, plasmin, and TLRs (Goldminz et al. ). A blockade of NF-κB signaling within various target cells leads to decrease production of pro-inflammatory cytokines.
The Janus kinase (JAK)/STAT signaling pathway is well known to be involved in many cellular processes including inflammation. The JAK/STAT pathway converts cytokine signals into genomic responses that regulate proliferation and differentiation of the immune cells (Kaminska and Swiatek-Machado ). JAK inhibitors may be a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory, and antiallergic properties. When keratinocytes from the psoriatic skin were cultured, a significant induction of the STAT1-induced transcriptional activity was stimulated with either IFN-γ or IFN-α (Hald et al. ).STAT3 are involved in the upregulation of keratin 17 (K17) expression induced by IL-22. Both STAT1 and STAT3 pathways are involved in the upregulation of K17 expression induced by IL-17A, and this regulation could be partially suppressed by STAT1 or STAT3 small interfering RNAs and inhibitors (Shi et al. ). Taken together, these cellular signaling pathways, which have been shown to be involved in the progression of psoriasis, present potential targets for new prosiasis therapies.
Linkage and candidate gene association study
Although psoriasis has a multifactorial etiology, it is strongly influenced by genetic factors (Lowes et al. ). Compared with the general population, a higher incidence of the disease has been identified among first-degree and second-degree relatives of psoriasis. The risk of psoriasis is greater in monozygotic twins than in dizygotic twins, confirming the genetic basis of the disease (Nestle et al. ). Prior traditional approaches, such as family-based linkage studies and population-based candidate gene association studies, have had some success in identifying genetic risk factors. The major locus strongly associated with psoriasis is PSORS1 on chromosome 6p21, spanning approximately 300 kb of the MHC class I region (Veal et al. ). Large-scale resequencing has established HLA-C and its HLA-Cw*06 allele as the most likely PSORS1 candidate genes (Nair et al. ). Variants associated with the HLA-Cw*06 allele contribute to one-third and one-half of the genetic susceptibility to psoriasis (Elder ) and are determinant for the development of early-onset psoriasis (Zhang et al. ).
In addition to PSORS1, linkage analyses and association studies have highlighted psoriasis loci on several other chromosomes outside of the MHC region, designated PSORS2-PSORS10 (Bowcock and Krueger ; Perera et al. ). PSORS2 was localized to the chromosomal region 17q25.3 in a family of European ancestry and has also been observed in a Taiwanese family with multiple psoriasis-affected members (Jordan et al. ). Two disease-causing CARD14 mutations in psoriasis identified by using genomic capture and DNA sequencing suggest that the involvement of PSORS2 is due to the mutation of this gene (Jordan et al. ). In the PSORS3 locus, on chromosome 4q (Matthews et al. ), evidence from an association study suggests a putative association between the interferon regulatory factor 2 (IRF2) and psoriasis, which indicates that the IRF2 gene as a candidate for PSORS3 (Foerster et al. ). PSORS4 is in the 1q21 region (Matthews et al. ), where a common deletion (LCE3C_LCE3B-del) in the late cornified envelope (LCE) cluster is associated with psoriasis (Coto et al. ). The locus, PSORS5, on chromosome 3q21 has been found in family-based analysis studies (Enlund et al. ). The cystatin A, zinc finger protein 148, and solute carrier family 12 member A8 (SLC12A8) genes are proposed as candidate genes at the psoriasis susceptibility locus PSORS5 (Samuelsson et al. ; Huffmeier et al. ). PSORS6, located at 19p13 (Lee et al. ), has been suggested to interact with PSORS1 (Huffmeier et al. ). PSORS7 at 1p (Veal et al. ), PSORS8 at 16q (Nair et al. ), and PSORS9 at 4q31-34 (Yan et al. ; Zhang et al. ) are all linked to psoriasis. Although other susceptibility loci and genes have also been postulated, it is difficult to replicate the results of these studies, a result of interethnic differences and environmental variations.
Genome-wide association studies
GWAS have become an effective approach for identifying genetic variants associated with disease risk (Price et al. ). To date, several large GWAS for psoriasis in both the European and Asian populations have been performed (Nair et al. ; Zhang et al. ; Ellinghaus et al. ; Huffmeier et al. ; Strange et al. ; Stuart et al. ; Sun et al. ; Tsoi et al. ) to identify novel susceptibility genes and mechanisms associated with psoriasis with kinds of algorithms (Tables 1 and 2). It is worth mentioning that the most highly significant associated single nucleotide polymorphisms (SNPs) in different populations are localized in the MHC class I region, which encodes the HLA molecules HLA-A, HLA-B, and HLA-C. The findings of GWAS pertaining to psoriasis and psoriatic arthritis GWAS (Liu et al. ) demonstrate that the strongest associated SNP alleles are highly correlated with the HLA-Cw*06, which is consistent with the previously described involvement of the PSORS1 region. Through in-depth analyses of the GWAS data, two additional susceptibility loci within the HLA region have been shown to confer risk of psoriasis in both Chinese and European lineages (Feng et al. ).
The GWAS of psoriasis patients have implicated several other susceptibility genes that are involved in various biological processes, including the IL-23/Th17 pathway (Ellinghaus et al. ; Huffmeier et al. ; Nair et al. ; Strange et al. ), NF-κB signaling (Nair et al. ; Strange et al. ; Stuart et al. ), epidermal cell differentiation (de Cid et al. ; Sun et al. ; Zhang et al. ), MHC class I processing (Strange et al. ; Sun et al. ), the ubiquitin pathway (Capon et al. ; Sun et al. ), and Th2-type response (Nair et al. ) as well as genes with yet unknown functions. As mentioned above, the functional role of IL-23-induced and Th17 cell-mediated chronic inflammation is highlighted in the immune-pathogenesis of psoriasis. In GWAS findings of both European and Chinese populations, different SNP alleles associated with psoriasis in and upstream of the IL12B gene and the IL23R gene have been identified, confirming the role of the IL-23/Th17 axis in psoriasis pathogenesis (Cargill et al. ; Nair et al. ; Zhang et al. ). IL12B (encoding the p40 subunit of IL-23 and IL-12) and IL23A (encoding the p19 subunit of IL-23) are heterodimerize to form IL-23. The IL-23/Th17 pathway signaling could promote cellular immune responses by strengthening of a subset of IL-17-expressing T cells (Bettelli et al. ) or dysregulation of expression ultimately resulting in psoriasis.
Several mediators of the NF-κB signaling pathways are linked to psoriasis (Goldminz et al. ). As revealed by GWAS, TNFAIP3 (TNF-α-induced protein 3) and TNIP1 (TNFAIP3-interacting protein 1), the gene products of which modulate this pathway show a strong association with the disease (Elder ; Nair et al. ). Genetic variants in the TRAF3IP2 (TRAF3-interacting protein 2),which encodes a protein involved in IL-17 signaling, are implicated in psoriasis susceptibility (Ellinghaus et al. ; Huffmeier et al. ). TRAF3IP2 interacts with tumor necrosis factor receptor-associated factor (TRAF) proteins and either I-êB kinase or mitogen-activated protein kinase to activate either NF-κB or Jun kinase (Ellinghaus et al. ). Encoding endoplasmic reticulum aminopeptidase 1 (ERAP1), located in 5q15 associated region, which encodes an amino peptidase regulatory factor for the quality of peptides bound to MHC class I molecules, is implicated in psoriasis in both European and Chinese populations (Strange et al. ; Sun et al. ). Compelling evidence shows that it exits the interaction between the HLA-C and ERAP1 loci in the psoriasis pathogenesis process. ERAP1 variants could influence psoriasis susceptibility in individuals who carry the HLA-C risk allele (Strange et al. ).Variants of the gene encoding zinc-finger protein 313 (ZNF313) are also associated with psoriasis as well (Capon et al. ). ZNF313 has a similar role of as the ubiquitin ligase of TRAC-1 to regulate T cell activation. The present data also provide evidences that skin barrier function plays a role in psoriasis susceptibility. A deletion polymorphism of two genes (LCE3C and LCE3B) is associated with psoriasis in different populations (de Cid et al. ; Zhang et al. ). The LCE genes encode the stratum corneum proteins of the cornified envelope, which is important in epidermal terminal differentiation (Mischke et al. ). Genetic susceptibility variant(s) within the LCE genes may influence the development of psoriasis by interrupting the terminal differentiation of keratinocytes. Collectively, the genetic determinants could lead to dysregulation of innate and adaptive immunity and to epidermal barrier dysfunction in disease process.
Common genetic factors in autoimmune or inflammatory diseases
To evaluate the relationship between psoriasis and autoimmune disease, the findings of one retrospective study suggest that psoriasis patients are more likely to be diagnosed with an autoimmune disease than individuals without psoriasis (Wu et al. ). Common autoimmune or inflammatory (immune-mediated) diseases, such as RA, CD, MS, celiac disease (CeD), inflammatory bowel disease (IBD), ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE), are highly prevalent in psoriasis patients. Psoriasis and psoriatic arthritis (PsA) are interrelated disorders that share pathophysiological mechanisms. The occurrence of psoriasis in conjunction with chronic inflammatory arthritis is range from 10% to 30% of individuals with the disease.
Many confirmed and nominally associated psoriasis susceptibility loci show a high level of overlap with the associated loci of other autoimmune diseases. This marked overlap of autoimmune disease susceptibility loci may occur when the same variants contribute to multiple diseases or when different variants in the same gene confer susceptibility to various autoimmune diseases. Typically, psoriasis is concomitant with autoimmune and inflammatory diseases (Makredes et al. ), sharing many susceptibility genes between them (Table 3). Several associated genes are also implicated in other immune-mediated disorders, notably CD (Ellinghaus et al. ), offering insights into the postulated shared pathogenesis of CD and PS. In addition to psoriasis, IL23R is associated with IBD, PsA, and MS (Duerr et al. ; Begovich et al. ; Liu et al. ), highlighting the functional role of the IL-23/Th17 axis in immune-mediated inflammatory and autoimmune processes. Furthermore, many genes involved in the NF-κB pathway, such as TNFAIP3 and NFKB1A, are also linked to risk for other autoimmune diseases (Fung et al. ; Han et al. ; Bowes et al. ; Li et al. ). Although HLA-C remains the strongest susceptibility candidate gene in psoriasis, evidences for an interaction between HLA-C and other autoimmune diseases have been confirmed by GWAS (Raychaudhuri et al. ). These and other regions of genetic association shared with autoimmune diseases indicate that psoriasis may have similar immune mechanism and pathogenic pathways. However, common susceptibility genes among different phenotypes suggest that genetic variation may influence the entire pathways to increase the risk for multiple diseases.
Our understanding of the genetic basis of psoriasis has been rapidly advanced by GWAS approach. More than 40 robust susceptibility loci have been identified and confirmed to be associated with psoriasis using this technique. However, most of the identified risk variants are expected to be tagged as SNPs, and the functional coding variants of these susceptibility genes, particularly those that are of low frequency and rare, are largely refractory to the interrogation by GWAS. Therefore, such variants have not been systematically investigated. With the development of technologies for next-generation sequencing (NGS) technologies, such as exome sequencing analysis, the systematic investigation of coding variants is possibly. Recently, a large-scale sequencing analysis of functional coding variants was performed to investigate the contribution of functional coding variants to the genetic susceptibility of psoriasis in a Han Chinese population, identifying seven common and low-frequency nonsynonymous variants within known psoriasis susceptibility genes, including IL23R, GJB2, LCE3D, ERAP1, CARD14, and ZNF816A, that are associated with psoriasis risk (Tang et al. ).
The pathogenesis of psoriasis involves a complicated interaction between genetic and immunological and environmental components. During recent years, there have been great advances and tremendous achievements in immunity and genetic research on psoriasis that have contributed to the understanding of the mechanism of psoriasis. It is clear that Th1, Th17, and Th22 cells, which interact with each other, mediate the immunity response in disease development. Recent GWAS have identified a variety of genetic components involving both the immune system and the epidermis that affect psoriasis pathogenesis. Several genetic factors and pathways shared with autoimmune and inflammatory (immune-mediated) diseases highlight a common mechanism in different diseases. However, a substantial proportion of the involved genetic factors have yet to be identified, and it is difficult to clarify how these genetic factors and pathways intersect and contribute to inflammation, proliferation, and altered differentiation in psoriasis. Fine mapping and resequencing efforts, together with extensive functional studies, are required to detect all potential causal variants for the susceptibility to psoriasis. Recent advances in next-generation sequencing technologies will enable the increased understanding of the pathogenetic mechanisms and will position a number of confirmed genes or pathways as potential targets for future therapeutic intervention.
LDS M.D. Ph.D is a Professor of Dermatology, Assistant Director, Key Lab of Dermatology, Ministry of Education, Committee Member of Youth Commission of Genetics of China, Committee Member of Human and Medical Genetics of Genetics Society of China, and Director of Research Department at the First Affiliated Hospital of Anhui Medical University.
XJZ M.D. Ph.D is a Professor of Dermatology, Director of Institute of Dermatology, Anhui Medical University, Director of Key Lab of Dermatology, Ministry of Education, President of Chinese Society of Dermatology, Board of Director, International League of Dermatological Societies, President of Asian Dermatological Association, Associate editor, Journal of Investigative Dermatology, Editorial Advisory Board Member, British Journal of Dermatology, Editorial Board Member, Journal of Dermatological Science, Editorial Board Member, and International Journal of Dermatology.
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This work was supported by the National Science Fund for Excellent Young Scholars (81222022) and the Outstanding Talents of Organization Department of the CPC (Communist Party of China) Central Committee program.
The authors declare that they have no competing interests.
XJZ conceived of the review and participated in its design and coordination. LDS designed the review, drafted the manuscript, and gave the final approval of the version to be published. Both authors read and approved the final manuscript.