Open Access

The immunological and genetic aspects in psoriasis

Applied Informatics20141:3

https://doi.org/10.1186/s40535-014-0003-1

Received: 19 July 2014

Accepted: 25 October 2014

Published: 31 December 2014

Abstract

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.

Keywords

Psoriasis Immunity Genetics Pathogenesis

Review

Introduction

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 [2003]). Symptoms typically develop in early adulthood, between the age of 15 and 25 years old (Henseler and Christophers [1985]), 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 [2007]), and at least 10% to 30% of patients develop arthritis (Nickoloff and Nestle [2004]; Ibrahim et al. [2009]). 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. [2009]) 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 [1998]). 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. [2002]; Nair et al. [2006]). 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. [2008]). 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 [2006]). 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 [2005]). 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. [2007]). Therefore, it fits the definition of an autoimmune disease (Davidson and Diamond [2001]). 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.

Immunological factors

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 [2002]; Cai et al. [2012]). Evidence for the central role of T lymphocytes has been found in animal models of psoriasis (Boehncke and Schon [2007]), successful treatment of psoriasis patients with cyclosporine A to inhibit T cell proliferation and cytokine production (Mueller and Herrmann [1979]) and specifically recruited T cell clones that permanently involve the psoriatic inflammation (Vollmer et al. [2001]). 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. [2007]). 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. [2007]). 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. [1999]; Friedrich et al. [2000]). 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. [2004]). 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 [2005]).Upon activation, KCs express a plethora of cytokines, chemokines, and accessory molecules, transmitting both positive and negative signals to immune cells (Albanesi et al. [2005]). KCs also produce endothelial cell mitogens such as VEGF and PDGF, leading to angiogenesis (Costa et al. [2007]).

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. [1994]). 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. [2005]). Myeloid DCs, which are activated by PDCs and keratinocyte-derived cytokines, are also accumulated in the psoriatic tissues (Zaba et al. [2009]) and are believed to be required for sustaining and amplifying the T cell inflammatory reaction (Chu et al. [2011]). 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. [2011]). 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. [2009]).

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. [1993]). A role for LCs has been indicated in the pathogenesis of psoriasis (Cumberbatch et al. [2006]), inducing the generation of distinct IL-22-producing Th22 cells infiltrating into the skin (Fujita et al. [2009]). Macrophages can contribute to both epithelial-based and T cell-mediated pathways of inflammation in psoriasis (Clark and Kupper [2006]). 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. [2006]). 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. [2009]).

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. [1993]; Schlaak et al. [1994]). 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. [1994]; Schlaak et al. [1994]; Austin et al. [1999]). Th17 cells, a newly appreciated T cell subset that produce IL-17 (Miossec et al. [2009]) and IL-22 (Liang et al. [2006]), 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. [2008]), as well as CCL20, which draws CCR6+ cells into sites of inflammation (Harper et al. [2009]). A mixed Th1 and Th17 inflammatory environment is found in the affected skin during the disease process (Lowes et al. [2008]). IL-23, which is composed of two subunits, a unique p19 subunit and a p40 subunit shared with IL-12 (Lee et al. [2004]), 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. [2004]) 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. [2009]; Nakajima [2012]). 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. [2012]). IL-22 is a member of the IL-10 cytokine family, which is primarily secreted by Th17 cells (Trifari et al. [2009]). 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. [2007]; Zheng et al. [2007]). 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. [1994]). 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 [2005]).

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. [2012]). 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 [2004]). 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.

Inflammation pathways

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. [2004]). 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. [2007]). 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. [2006]). 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 [2008]). 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 [2006]).

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. [2013]). 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. [2013]). 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. [2005]). 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. [2013]). 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 [2008]). 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. [2013]).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. [2011]). 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.

Genetic factors

Linkage and candidate gene association study

Although psoriasis has a multifactorial etiology, it is strongly influenced by genetic factors (Lowes et al. [2007]). 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. [2009]). 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. [2002]). Large-scale resequencing has established HLA-C and its HLA-Cw*06 allele as the most likely PSORS1 candidate genes (Nair et al. [2006]). Variants associated with the HLA-Cw*06 allele contribute to one-third and one-half of the genetic susceptibility to psoriasis (Elder [2006]) and are determinant for the development of early-onset psoriasis (Zhang et al. [2003]).

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 [2005]; Perera et al. [2012]). 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. [2012]). 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. [2012]). In the PSORS3 locus, on chromosome 4q (Matthews et al. [1996]), 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. [2004]). PSORS4 is in the 1q21 region (Matthews et al. [1996]), where a common deletion (LCE3C_LCE3B-del) in the late cornified envelope (LCE) cluster is associated with psoriasis (Coto et al. [2011]). The locus, PSORS5, on chromosome 3q21 has been found in family-based analysis studies (Enlund et al. [1999]). 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. [2004]; Huffmeier et al. [2005]). PSORS6, located at 19p13 (Lee et al. [2000]), has been suggested to interact with PSORS1 (Huffmeier et al. [2009]). PSORS7 at 1p (Veal et al. [2001]), PSORS8 at 16q (Nair et al. [1997]), and PSORS9 at 4q31-34 (Yan et al. [2007]; Zhang et al. [2007]) 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. [2010]). To date, several large GWAS for psoriasis in both the European and Asian populations have been performed (Nair et al. [2009]; Zhang et al. [2009]; Ellinghaus et al. [2010]; Huffmeier et al. [2010]; Strange et al. [2010]; Stuart et al. [2010]; Sun et al. [2010]; Tsoi et al. [2012]) 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. [2008]) 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. [2009]).
Table 1

The genetic loci associated with psoriasis identified by GWAS

Chromosomal

Reported gene(s)

SNP

Context

P value

Odds ratio (95% CI)

Population

Ref.

1q21.3

LCE3B, LCE3D

rs6677595

Intergenic

2.1 × 10−33

1.26 [NR]

European

(Tsoi et al. [2012])

LCE3D, LCE3A

rs4085613

Intergenic

7 × 10−30

1.32 [1.25 to 1.39]

Chinese

(Zhang et al. [2009])

LCE3D

rs4112788

Intergenic

3 × 10−10

1.29 [1.19 to 1.40]

European

(Strange et al. [2010])

1p36.23

SLC45A1, TNFRSF9

rs11121129

Intergenic

1.7 × 10−8

1.13 [NR]

European

(Tsoi et al. [2012])

1p36.11

RUNX3

rs7536201

nearGene-5

2.3 × 10−12

1.13 [NR]

European

IL28RA

rs7552167

Intergenic

8.5 × 10−12

1.21 [NR]

European

rs4649203

Intergenic

7 × 10−8

1.13 [1.05 to 1.22]

European

(Strange et al. [2010])

3.91 × 10−12

1.16 [NR]

Chinese

(Cheng et al. [2013])

1p31.3

IL23R

rs2201841

Intron

1.75× 10−10

1.23 [NR]

European

(Elder [2009])

rs9988642

nearGene-3

1.1 × 10−26

1.52 [NR]

European

(Tsoi et al. [2012])

rs11209026

Missense

7 × 10−7

1.49 [1.27 to 1.74]

European

(Strange et al. [2010])

rs2201841

Intron

3 × 10−8

1.13 [NR]

European

(Nair et al. [2009])

2q24.3

IFIH1

rs17716942

Intron

1 × 10−13

1.29 [1.17 to 1.43]

European

(Strange et al. [2010])

2p16.1

FLJ16341, REL

rs62149416

Intergenic

1.8 × 10−17

1.17 [NR]

European

(Tsoi et al. [2012])

REL

rs702873

Intron

4 × 10−9

1.12 [1.04 to 1.20]

European

(Strange et al. [2010])

NR

rs842636

Intron

6 × 10−6

1.15 [NR]

European

(Stuart et al. [2010])

2p15

B3GNT2

rs10865331

Intergenic

4.7 × 10−10

1.12 [NR]

European

(Tsoi et al. [2012])

5q33.3

PTTG1

rs2431697

Intergenic

1.11 × 10−8

1.20 [1.13 to 1.28]

Chinese

(Sun et al. [2010])

IL12B

rs12188300

Intergenic

3.2 × 10−53

1.58 [NR]

European

(Tsoi et al. [2012])

rs2546890

ncRNA

1 × 10−20

1.54 [1.32 to 1.79]

European

(Ellinghaus et al. [2010])

rs3213094

Intron

5 × 10−11

1.39 [1.26 to 1.53]

European

(Strange et al. [2010])

rs2082412

Intergenic

2 × 10−28

1.44 [NR]

European

(Nair et al. [2009])

rs3213094

Intron

3 × 10−26

1.28 [1.23 to 1.35]

Chinese

(Zhang et al. [2009])

rs2082412

Intergenic

4.75× 10−18

1.42 [NR]

European

(Elder [2009])

5q33.1

TNIP1/ANXA6

rs3762999

Intergenic

4.55 × 10−18

1.23 [1.18 to 1.29]

Chinese

(Sun et al. [2010])

rs999556

Intergenic

3.83 × 10−21

1.25 [1.20 to 1.31]

Chinese

TNIP1

rs17728338

Intergenic

1.4× 10−13

1.56 [NR]

European

(Elder [2009])

rs2233278

UTR-5

2.2 × 10−42

1.59 [NR]

European

(Tsoi et al. [2012])

rs17728338

Intergenic

1 × 10−20

1.59 [NR]

European

(Nair et al. [2009])

IL13, IL4

rs1295685

Intergenic

3.4 × 10−10

1.18 [NR]

European

(Tsoi et al. [2012])

IL13

rs20541

Missense

5 × 10−15

1.27 [NR]

European

(Nair et al. [2009])

5q15

ERAP1

rs27432

Intron

1.9 × 10−20

1.2 [NR]

European

(Tsoi et al. [2012])

rs27524

Intron

3 × 10−11

1.13 [1.05 to 1.22]

European

(Strange et al. [2010])

rs151823

Intergenic

9.32 × 10−9

0.89 [0.85 to 0.92]

Chinese

(Sun et al. [2010])

5q15

LNPEP

rs2303138

Missense

1.83 × 10−13

1.16 [NR]

Chinese

(Cheng et al. [2013])

6q25.4

EXOC2, IRF4

rs9504361

Intergenic

2.1 × 10−11

1.12 [NR]

European

(Tsoi et al. [2012])

6q25.3

TAGAP

rs2451258

Intergenic

3.4 × 10−8

1.12 [NR]

European

6q23.3

TNFAIP3

rs610604

Intron

3.07× 10−10

1.23 [NR]

European

(Elder [2009])

  

rs582757

Intron

2.2 × 10−25

1.23 [NR]

European

(Tsoi et al. [2012])

  

rs610604

Intron

9 × 10−12

1.19 [NR]

European

(Nair et al. [2009])

6q21

TRAF3IP2

rs33980500

Missense

4.2 × 10−45

1.52 [NR]

European

(Tsoi et al. [2012])

rs458017

Missense

2 × 10−16

1.37 [1.22 to 1.54]

European

(Strange et al. [2010])

rs13196377

Intron

1.39 × 10−12

1.67 [1.45 to 1.93]

European

(Huffmeier et al. [2010])

rs13190932

Intron

8.56 × 10−17

1.83 [1.59 to 2.12]

European

rs13210247

Missense

1.73 × 10−14

1.69 [1.48 to 1.94]

European

rs33980500

Missense

1 × 10−16

NR

European

(Ellinghaus et al. [2010])

rs240993

Intron

5 × 10−20

1.25 [1.16 to 1.34]

European

(Strange et al. [2010])

6p21.33

HLA-C

rs1265181

Intergenic

1.93 × 10−208

22.62 [NR]

Chinese

(Zhang et al. [2009])

rs12191877

Intergenic

2.98× 10−178

2.87 [NR]

European

(Elder [2009])

rs13191343

Intergenic

2.32 × 10−72

2.37 [2.16 to 2.61]

European

(Huffmeier et al. [2010])

rs12191877

Intergenic

4 × 10−32

2.79 [2.35 to 3.33]

European

(Ellinghaus et al. [2010])

rs10484554

Intergenic

4 × 10−214

4.66 [4.23 to 5.13]

European

(Strange et al. [2010])

rs12191877

Intergenic

1 × 10−100

2.64 [NR]

European

(Nair et al. [2009])

rs10484554

Intergenic

2 × 10−39

2.8 [2.40 to 3.30]

European

(Liu et al. [2008])

rs3134792

Intergenic

1 × 10−9

NR

European

(Capon et al. [2008])

HLA-B, HLA-C

rs4406273

Intergenic

4.5 × 10−723

4.32 [NR]

European

(Tsoi et al. [2012])

HCP5

rs2395029

ncRNA

2 × 10−26

4.1 [3.10 to 5.30]

European

(Liu et al. [2008])

7p14.1

ELMO1

rs2700987

Intron

4.3 × 10−9

1.11 [NR]

European

(Tsoi et al. [2012])

8p23.2

CSMD1

rs7007032

Intron

3.78 × 10−8

1.16 [1.10 to 1.22]

Chinese

(Sun et al. [2010])

rs10088247

Intron

4.54 × 10−9

1.17 [1.11 to 1.23]

Chinese

9q34.13

TSC1

rs1076160

Intron

6 × 10−6

1.09 [NR]

European

(Nair et al. [2009])

9q31.2

KLF4

rs10979182

Intergenic

2.3 × 10−8

1.12 [NR]

European

(Tsoi et al. [2012])

9p21.1

DDX58

rs11795343

Intron

8.4 × 10−11

1.11 [NR]

European

10q22.3

ZMIZ1

rs1250546

Intron

6.8 × 10−7

1.1 [NR]

European

11q24.3

ETS1

rs3802826

Intron

9.5 × 10−10

1.12 [NR]

European

ZC3H12C

rs4561177

nearGene-5

7.7 × 10−13

1.14 [NR]

European

11q13.1

RPS6KA4, PRDX5

rs645078

Intergenic

2.2 × 10−6

1.09 [NR]

European

12q13.3

STAT2, IL23A

rs2066819

Intergenic

5.4 × 10−17

1.39 [NR]

European

IL23A, STAT2

rs2066808

Intron

1 × 10−9

1.34 [NR]

European

(Nair et al. [2009])

IL23A

rs2066807

Missense

1.9× 10−5

1.33 [NR]

European

(Elder [2009])

rs2066808

Intron

2 × 10−7

1.49 [1.28 to 1.73]

European

(Strange et al. [2010])

12q13.2

RPS26

rs12580100

Intergenic

1 × 10−6

1.17 [NR]

European

(Stuart et al. [2010])

13q14.11

COG6

rs7993214

Intron

2 × 10−6

1.41 [1.22 to 1.61]

European

(Liu et al. [2008])

GJB2

rs3751385

UTR-3

8.57 × 10−8

0.87 [0.84 to 0.91]

Chinese

(Sun et al. [2010])

14q13.2

NFKBIA, PSMA6

rs12586317

Intron

2 × 10−8

1.15 [NR]

European

(Stuart et al. [2010])

NFKBIA

rs8016947

Intergenic

2 × 10−11

1.19 [1.11 to 1.27]

European

(Strange et al. [2010])

3.9 × 10−10

1.12 [NR]

Chinese

(Li et al. [2013])

16p13.13

PRM3, SOCS1

rs367569

Intergenic

4.9 × 10−8

1.13 [NR]

European

(Tsoi et al. [2012])

16p11.2

PRSS53, FBXL19

rs12445568

Intergenic

1.2 × 10−16

1.16 [NR]

European

FBXL19, POL3S

rs10782001

Intron

9 × 10−10

1.16 [NR]

European

(Stuart et al. [2010])

17q25.3

CARD14

rs11652075

Missense

3.4 × 10−8

1.11 [NR]

European

(Tsoi et al. [2012])

17q21.2

PTRF, STAT3, STAT5A/B

rs963986

Intergenic

5.3 × 10−9

1.15 [NR]

European

17q11.2

NOS2

rs28998802

Intron

3.3 × 10−16

1.22 [NR]

European

rs4795067

Intron

4 × 10−11

1.19 [NR]

European

(Stuart et al. [2010])

NR

rs1975974

Intergenic

1 × 10-7

1.17 [NR]

European

18q22.1

SERPINB8

rs514315

nearGene-3

5.92 × 10−9

0.87 [0.83 to 0.91]

Chinese

(Sun et al. [2010])

18q21.2

POL1, STARD6, MBD2

rs545979

Intergenic

3.5 × 10−10

1.12 [NR]

European

(Tsoi et al. [2012])

19q13.41

ZNF816A

rs9304742

Intron

2.11 × 10−9

0.88 [0.84 to 0.92]

Chinese

(Sun et al. [2010])

19p13.2

ILF3, CARM1

rs892085

Intergenic

3.0 × 10−17

1.17 [NR]

European

(Tsoi et al. [2012])

TYK2

rs34536443

Missense

9.1 × 10−31

1.88 [NR]

European

rs12720356

Missense

4 × 10−11

1.4 [1.23 to 1.61]

European

(Strange et al. [2010])

rs280519

Intron

4 × 10−9

1.13 [1.05 to 1.21]

European

20q13.13

ZNF313

rs2235617

Intron

2 × 10−6

1.2 [1.11 to 1.30]

European

RNF114

rs1056198

Intron

1.5 × 10−14

1.16 [NR]

European

(Tsoi et al. [2012])

ZNF313

rs495337

Cds-synon

1 × 10−8

1.25 [1.12 to 1.39]

European

(Capon et al. [2008])

20q13.12

SDC4

rs1008953

Intergenic

1 × 10−7

1.14 [NR]

European

(Stuart et al. [2010])

22q11.21

UBE2L3

rs4821124

Intron

3.8 × 10−8

1.13 [NR]

European

(Tsoi et al. [2012])

NR, not reported; UTR, untranslated region; ncRNA, noncoding RNA; nearGene-5/3, a SNP close to the 5′ or 3′ end of a gene. Intergenic: a stretch of sequences located between genes.

Table 2

The algorithms of psoriasis GWAS

Chromosomal

Reported gene(s)

SNP

Algorithms

Ref.

1q21.3

LCE3B, LCE3D

rs6677595

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

LCE3D, LCE3A

rs4085613

Plink 1.02, PCA, Cochran-Armtiage trend test, Cochran-Mantel-Hanezel stratification analysis

(Zhang et al. [2009])

LCE3D

rs4112788

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

1p36.23

SLC45A1, TNFRSF9

rs11121129

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

1p36.11

RUNX3

rs7536201

IL28RA

rs7552167

rs4649203

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

PCA, PLINK 1.07, R, EIGENSTRAT, Cochran-Armitage trend test

(Cheng et al. [2013])

1p31.3

IL23R

rs2201841

Χ2 statistic, logistic regression , MACH

(Nair et al. [2009])

rs9988642

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

rs11209026

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

2q24.3

IFIH1

rs17716942

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

2p16.1

FLJ16341, REL

rs62149416

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

REL

rs702873

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

NR

rs842636

MACH version 1.0, Meta-analysis

(Stuart et al. [2010])

2p15

B3GNT2

rs10865331

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

5q33.3

PTTG1

rs2431697

R, PCA, Cochran-Armitage trend test, Heterogeneity tests

(Sun et al. [2010])

IL12B

rs12188300

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

rs2546890

MACH v.1.0.16, MACH2DAT, gPLINK v2.049, CopyCaller v1.0, METAL

(Ellinghaus et al. [2010])

rs3213094

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

rs2082412

Χ2 statistic, logistic regression , MACH

(Nair et al. [2009])

rs3213094

Plink 1.02, PCA, Cochran-Armtiage trend test, Cochran-Mantel-Hanezel stratification analysis

(Zhang et al. [2009])

5q33.1

TNIP1/ANXA6

rs3762999

R, PCA, Cochran-Armitage trend test, Heterogeneity tests

(Sun et al. [2010])

rs999556

TNIP1

rs17728338

Χ2 statistic, logistic regression , MACH

(Nair et al. [2009])

rs2233278

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

IL13, IL4

rs1295685

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

IL13

rs20541

Χ2 statistic, logistic regression , MACH

(Nair et al. [2009])

5q15

ERAP1

rs27432

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

rs27524

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

rs151823

R, PCA, Cochran-Armitage trend test, Heterogeneity tests

(Sun et al. [2010])

5q15

LNPEP

rs2303138

PCA, PLINK 1.07, R, EIGENSTRAT, Cochran-Armitage trend

(Cheng et al. [2013])

6q25.4

EXOC2, IRF4

rs9504361

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

6q25.3

TAGAP

rs2451258

6q23.3

TNFAIP3

rs582757

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

  

rs610604

Χ2 statistic, logistic regression , MACH

(Nair et al. [2009])

6q21

TRAF3IP2

rs33980500

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

rs458017

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

rs13196377

birdseed-v2 algorithm, MACH1, Χ2 test, Cochran-Mantel-Haenszel tests, PHASE

(Huffmeier et al. [2010])

rs13190932

rs13210247

rs33980500

MACH v.1.0.16, MACH2DAT, gPLINK v2.049, CopyCaller v1.0, METAL

(Ellinghaus et al. [2010])

rs240993

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

6p21.33

HLA-C

rs1265181

Plink 1.02, PCA, Cochran-Armtiage trend test, Cochran-Mantel-Hanezel stratification analysis

(Zhang et al. [2009])

rs13191343

birdseed-v2 algorithm, MACH1, Chi-Square test, Cochran-Mantel-Haenszel tests, PHASE

(Huffmeier et al. [2010])

rs12191877

MACH v.1.0.16, MACH2DAT, gPLINK v2.049, CopyCaller v1.0, METAL

(Ellinghaus et al. [2010])

rs10484554

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

rs12191877

Χ2 statistic, logistic regression , MACH

(Nair et al. [2009])

rs10484554

STRUCTURE, EIGENSTRAT, Cochran-Armitage Test, R, Haploview 3.2

(Liu et al. [2008])

rs3134792

Haploview software, Fisher's exact test, PLINK, I2 statistic

(Capon et al. [2008])

HLA-B, HLA-C

rs4406273

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

HCP5

rs2395029

STRUCTURE, EIGENSTRAT, Cochran-Armitage Test, R, Haploview 3.2

(Liu et al. [2008])

7p14.1

ELMO1

rs2700987

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

8p23.2

CSMD1

rs7007032

R, PCA, Cochran-Armitage trend test, Heterogeneity tests

(Sun et al. [2010])

rs10088247

9q34.13

TSC1

rs1076160

Χ2 statistic, logistic regression , MACH

(Nair et al. [2009])

9q31.2

KLF4

rs10979182

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

9p21.1

DDX58

rs11795343

10q22.3

ZMIZ1

rs1250546

11q24.3

ETS1

rs3802826

ZC3H12C

rs4561177

11q13.1

RPS6KA4, PRDX5

rs645078

12q13.3

STAT2, IL23A

rs2066819

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

IL23A, STAT2

rs2066808

Χ2 statistic, logistic regression , MACH

(Nair et al. [2009])

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

12q13.2

RPS26

rs12580100

Imputation(MACH software version 1.0), Meta-analysis

(Stuart et al. [2010])

13q14.11

COG6

rs7993214

STRUCTURE, EIGENSTRAT, Cochran-Armitage Test, R, Haploview 3.2

(Liu et al. [2008])

GJB2

rs3751385

R, PCA, Cochran-Armitage trend test, Heterogeneity tests

(Sun et al. [2010])

14q13.2

NFKBIA, PSMA6

rs12586317

Imputation(MACH software version 1.0), Meta-analysis

(Stuart et al. [2010])

NFKBIA

rs8016947

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

Cochran–Armitage trend test, Cochran–Mantel–Haenszel stratification analysis, PLINK 1.07, R 15.1

(Li et al. [2013])

16p13.13

PRM3, SOCS1

rs367569

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

16p11.2

PRSS53, FBXL19

rs12445568

FBXL19,POL3S

rs10782001

Imputation(MACH software version 1.0), Meta-analysis

(Stuart et al. [2010])

17q25.3

CARD14

rs11652075

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

17q21.2

PTRF, STAT3, STAT5A/B

rs963986

17q11.2

NOS2

rs28998802

rs4795067

Imputation(MACH software version 1.0), Meta-analysis

(Stuart et al. [2010])

NR

rs1975974

18q22.1

SERPINB8

rs514315

R, PCA, Cochran-Armitage trend test, Heterogeneity tests

(Sun et al. [2010])

18q21.2

POL1, STARD6, MBD2

rs545979

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

19q13.41

ZNF816A

rs9304742

R, PCA, Cochran-Armitage trend test, Heterogeneity tests

(Sun et al. [2010])

19p13.2

ILF3,CARM1

rs892085

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

TYK2

rs34536443

rs12720356

SNPTEST, R, IMPUTE2, PHASE, logistic regression

(Strange et al. [2010])

rs280519

20q13.13

ZNF313

rs2235617

RNF114

rs1056198

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

ZNF313

rs495337

Haploview software, Fisher's exact test, PLINK, I2 statistic

(Capon et al. [2008])

20q13.12

SDC4

rs1008953

Imputation(MACH software version 1.0), Meta-analysis

(Stuart et al. [2010])

22q11.21

UBE2L3

rs4821124

PLINK, minimac, IMPUTE2, PCA

(Tsoi et al. [2012])

PCA, principal-component analysis.

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. [2010]; Huffmeier et al. [2010]; Nair et al. [2009]; Strange et al. [2010]), NF-κB signaling (Nair et al. [2009]; Strange et al. [2010]; Stuart et al. [2010]), epidermal cell differentiation (de Cid et al. [2009]; Sun et al. [2010]; Zhang et al. [2009]), MHC class I processing (Strange et al. [2010]; Sun et al. [2010]), the ubiquitin pathway (Capon et al. [2008]; Sun et al. [2010]), and Th2-type response (Nair et al. [2009]) 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. [2007]; Nair et al. [2009]; Zhang et al. [2009]). 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. [2007]) or dysregulation of expression ultimately resulting in psoriasis.

Several mediators of the NF-κB signaling pathways are linked to psoriasis (Goldminz et al. [2013]). 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 [2009]; Nair et al. [2009]). 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. [2010]; Huffmeier et al. [2010]). 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. [2010]). 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. [2010]; Sun et al. [2010]). 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. [2010]).Variants of the gene encoding zinc-finger protein 313 (ZNF313) are also associated with psoriasis as well (Capon et al. [2008]). 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. [2009]; Zhang et al. [2009]). The LCE genes encode the stratum corneum proteins of the cornified envelope, which is important in epidermal terminal differentiation (Mischke et al. [1996]). 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. [2012]). 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. [2009]), sharing many susceptibility genes between them (Table 3). Several associated genes are also implicated in other immune-mediated disorders, notably CD (Ellinghaus et al. [2012]), 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. [2006]; Begovich et al. [2007]; Liu et al. [2008]), 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. [2009]; Han et al. [2009]; Bowes et al. [2010]; Li et al. [2013]). 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. [2012]). 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.
Table 3

Susceptibility genes in risk loci shared by autoimmune or inflammatory diseases

Region

Reported gene(s)

Biological annotations

Autoimmune and inflammatory diseases overlap

1p31.3

IL23R

IL-23/Th17 axis

PsV, AS, BD, CD, LE, UC

1p36.11

RUNX3

CD8+ T lymphocyte differentiation

PsV, CD, AS, CeD

2q24.2

IFIH1

Interferon signaling pathway

PsV, T1D, vitiligo

2p16.1

REL

Rel/NF-κB family

PsV, PA, CD, RA, CeD, IBD

5q33.3

IL12B

Th1 cell differentiation

PsV, CD, IBD, MS, PA, UC,

5q33.1

TNIP1

NF-κB pathway

PsV, IBD, SS, SLE, myasthenia gravis

5q31.1

IL13

Th2 cell differentiation

PsV, IBD, asthma, AD

5q15

ERAP1

MHC class I processing

PsV, AS, BD

6q23.3

TNFAIP3

NF-κB pathway

PsV, CeD, SLE, IBD, RA

6q21

TRAF3IP2

NF-κB pathway; IL-23/Th17 axis

PsV, IBD, PA

6p21.33

HLA-C

MHC class I processing

PsV, CD, PA, CRD, SJS-TEN, vitiligo

10q22.3

ZMIZ1

Inhibitor of activated STAT

PsV, MS, CD, vitiligo, CeD, IBD,

11q24.3

ETS1

Regulation of Th17 and B cells

PsV, SLE, CD, RA

16p13.13

SOCS1

IL-7RA/IL-7 pathway

PsV, MS, T1D

19p13.2

TYK2

IL-23/Th17 signaling

PsV, MS, T1D, CD

22q11.21

UBE2L3

Ubiquitin-conjugating enzyme

PsV, SLE, IBD, CeD, RA

(Using NHGR1 GWAS catalog data, http://www.genome.gov/gwastudies/). PsV, psoriasis vulgaris; PsA, psoriatic arthritis; AD, atopic dermatitis; IBD, inflammatory bowel disease; AS, ankylosing spondylitis; BD, Behcet's disease; CD, Crohn's disease; CeD, celiac disease; LE, leprosy; MS, multiple sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, systemic sclerosis; T1D, type I diabetes; UC, ulcerative colitis; SJS-TEN, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Next-generation sequencing

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. [2013]).

Conclusions

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.

Authors' information

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.

Declarations

Acknowledgements

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.

Authors’ Affiliations

(1)
Institute of Dermatology and Department of Dermatology at No.1 Hospital, Anhui Medical University
(2)
Key Laboratory of Dermatology, Anhui Medical University

References

  1. Albanesi C, Scarponi C, Giustizieri ML, Girolomoni G: Keratinocytes in inflammatory skin diseases. Curr Drug Targets Inflamm Allergy 2005,4(3):329–334.Google Scholar
  2. Arthur JS, Darragh J: Signaling downstream of p38 in psoriasis. J Invest Dermatol 2006,126(8):1689–1691. doi:10.1038/sj.jid.5700280Google Scholar
  3. Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG: The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 1999,113(5):752–759. doi:10.1046/j.1523–1747.1999.00749.xGoogle Scholar
  4. Begovich AB, Chang M, Caillier SJ, Lew D, Catanese JJ, Wang J, Hauser SL, Oksenberg JR: The autoimmune disease-associated IL12B and IL23R polymorphisms in multiple sclerosis. Hum Immunol 2007,68(11):934–937. doi:10.1016/j.humimm.2007.09.005Google Scholar
  5. Bettelli E, Oukka M, Kuchroo VK: T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007,8(4):345–350. doi:10.1038/ni0407–345Google Scholar
  6. Bhalerao J, Bowcock AM: The genetics of psoriasis: a complex disorder of the skin and immune system. Hum Mol Genet 1998,7(10):1537–1545.Google Scholar
  7. Boehncke WH, Schon MP: Animal models of psoriasis. Clin Dermatol 2007,25(6):596–605. doi:10.1016/j.clindermatol.2007.08.014Google Scholar
  8. Boniface K, Guignouard E, Pedretti N, Garcia M, Delwail A, Bernard FX, Nau F, Guillet G, Dagregorio G, Yssel H, Lecron JC, Morel F: A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clin Exp Immunol 2007,150(3):407–415. doi:10.1111/j.1365–2249.2007.03511.xGoogle Scholar
  9. Bowcock AM, Krueger JG: Getting under the skin: the immunogenetics of psoriasis. Nat Rev Immunol 2005,5(9):699–711. doi:10.1038/nri1689Google Scholar
  10. Bowes J, Lawrence R, Eyre S, Panoutsopoulou K, Orozco G, Elliott KS, Ke X, Morris AP, Thomson W, Worthington J, Barton A, Zeggini E: Rare variation at the TNFAIP3 locus and susceptibility to rheumatoid arthritis. Hum Genet 2010,128(6):627–633. doi:10.1007/s00439–010–0889–1Google Scholar
  11. Cai Y, Fleming C, Yan J: New insights of T cells in the pathogenesis of psoriasis. Cell Mol Immunol 2012,9(4):302–309. doi:10.1038/cmi.2012.15Google Scholar
  12. Capon F, Bijlmakers MJ, Wolf N, Quaranta M, Huffmeier U, Allen M, Timms K, Abkevich V, Gutin A, Smith R, Warren RB, Young HS, Worthington J, Burden AD, Griffiths CE, Hayday A, Nestle FO, Reis A, Lanchbury J, Barker JN, Trembath RC: Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. Hum Mol Genet 2008,17(13):1938–1945. doi:10.1093/hmg/ddn091Google Scholar
  13. Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, Matsunami N, Ardlie KG, Civello D, Catanese JJ, Leong DU, Panko JM, McAllister LB, Hansen CB, Papenfuss J, Prescott SM, White TJ, Leppert MF, Krueger GG, Begovich AB: A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 2007,80(2):273–290. doi:10.1086/511051Google Scholar
  14. Cheng H, Li Y, Zuo XB, Tang HY, Tang XF, Gao JP, Sheng YJ, Yin XY, Zhou FS, Zhang C, Chen G, Zhu J, Qian P, Liang B, Zheng XD, Li P, Ding YT, Cheng F, Luo J, Chang RX, Pan GB, Fan X, Wang ZX, Zhang AP, Liu JJ, Yang S, Sun LD, Zhang XJ (2013) Identification of a missense variant in LNPEP that confers psoriasis risk. J Invest Dermatol. doi:10.1038/jid.2013.317Google Scholar
  15. Chu CC, Di Meglio P, Nestle FO: Harnessing dendritic cells in inflammatory skin diseases. Semin Immunol 2011,23(1):28–41. doi:10.1016/j.smim.2011.01.006Google Scholar
  16. Clark RA, Kupper TS: Misbehaving macrophages in the pathogenesis of psoriasis. J Clin Invest 2006,116(8):2084–2087. doi:10.1172/jci29441Google Scholar
  17. Costa C, Incio J, Soares R: Angiogenesis and chronic inflammation: cause or consequence? Angiogenesis 2007,10(3):149–166. doi:10.1007/s10456–007–9074–0Google Scholar
  18. Coto E, Santos-Juanes J, Coto-Segura P, Alvarez V: New psoriasis susceptibility genes: momentum for skin-barrier disruption. J Invest Dermatol 2011,131(5):1003–1005. doi:10.1038/jid.2011.14Google Scholar
  19. Cumberbatch M, Singh M, Dearman RJ, Young HS, Kimber I, Griffiths CE: Impaired Langerhans cell migration in psoriasis. J Exp Med 2006,203(4):953–960. doi:10.1084/jem.20052367Google Scholar
  20. Davidson A, Diamond B: Autoimmune diseases. N Engl J Med 2001,345(5):340–350. doi:10.1056/nejm200108023450506Google Scholar
  21. de Cid R, Riveira-Munoz E, Zeeuwen PL, Robarge J, Liao W, Dannhauser EN, Giardina E, Stuart PE, Nair R, Helms C, Escaramis G, Ballana E, Martin-Ezquerra G, den Heijer M, Kamsteeg M, Joosten I, Eichler EE, Lazaro C, Pujol RM, Armengol L, Abecasis G, Elder JT, Novelli G, Armour JA, Kwok PY, Bowcock A, Schalkwijk J, Estivill X: Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet 2009,41(2):211–215. doi:10.1038/ng.313Google Scholar
  22. Di Cesare A, Di Meglio P, Nestle FO: The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol 2009,129(6):1339–1350. doi:10.1038/jid.2009.59Google Scholar
  23. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006,314(5804):1461–1463. doi:10.1126/science.1135245Google Scholar
  24. Elder JT: PSORS1: linking genetics and immunology. J Invest Dermatol 2006,126(6):1205–1206. doi:10.1038/sj.jid.5700357Google Scholar
  25. Elder JT: Genome-wide association scan yields new insights into the immunopathogenesis of psoriasis. Genes Immun 2009,10(3):201–209. doi:10.1038/gene.2009.11Google Scholar
  26. Ellinghaus E, Ellinghaus D, Stuart PE, Nair RP, Debrus S, Raelson JV, Belouchi M, Fournier H, Reinhard C, Ding J, Li Y, Tejasvi T, Gudjonsson J, Stoll SW, Voorhees JJ, Lambert S, Weidinger S, Eberlein B, Kunz M, Rahman P, Gladman DD, Gieger C, Wichmann HE, Karlsen TH, Mayr G, Albrecht M, Kabelitz D, Mrowietz U, Abecasis GR, Elder JT, et al.: Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat Genet 2010,42(11):991–995. doi:10.1038/ng.689Google Scholar
  27. Ellinghaus D, Ellinghaus E, Nair RP, Stuart PE, Esko T, Metspalu A, Debrus S, Raelson JV, Tejasvi T, Belouchi M, West SL, Barker JN, Koks S, Kingo K, Balschun T, Palmieri O, Annese V, Gieger C, Wichmann HE, Kabesch M, Trembath RC, Mathew CG, Abecasis GR, Weidinger S, Nikolaus S, Schreiber S, Elder JT, Weichenthal M, Nothnagel M, Franke A: Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Genet 2012,90(4):636–647. doi:10.1016/j.ajhg.2012.02.020Google Scholar
  28. Enlund F, Samuelsson L, Enerback C, Inerot A, Wahlstrom J, Yhr M, Torinsson A, Riley J, Swanbeck G, Martinsson T: Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden. Eur J Hum Genet 1999,7(7):783–790. doi:10.1038/sj.ejhg.5200365Google Scholar
  29. Ettehadi P, Greaves MW, Wallach D, Aderka D, Camp RD: Elevated tumour necrosis factor-alpha (TNF-alpha) biological activity in psoriatic skin lesions. Clin Exp Immunol 1994,96(1):146–151.Google Scholar
  30. Feng BJ, Sun LD, Soltani-Arabshahi R, Bowcock AM, Nair RP, Stuart P, Elder JT, Schrodi SJ, Begovich AB, Abecasis GR, Zhang XJ, Callis-Duffin KP, Krueger GG, Goldgar DE: Multiple loci within the major histocompatibility complex confer risk of psoriasis. PLoS Genet 2009,5(8):e1000606. doi:10.1371/journal.pgen.1000606Google Scholar
  31. Foerster J, Nolte I, Schweiger S, Ehlert C, Bruinenberg M, Spaar K, van der Steege G, Mulder M, Kalscheuer V, Moser B, Kijas Z, Seeman P, Stander M, Sterry W, te Meerman G: Evaluation of the IRF-2 gene as a candidate for PSORS3. J Invest Dermatol 2004,122(1):61–64. doi:10.1046/j.0022–202X.2003.22104.xGoogle Scholar
  32. Friedrich M, Krammig S, Henze M, Docke WD, Sterry W, Asadullah K: Flow cytometric characterization of lesional T cells in psoriasis: intracellular cytokine and surface antigen expression indicates an activated, memory/effector type 1 immunophenotype. Arch Dermatol Res 2000,292(10):519–521.Google Scholar
  33. Fujita H, Nograles KE, Kikuchi T, Gonzalez J, Carucci JA, Krueger JG: Human Langerhans cells induce distinct IL-22-producing CD4+ T cells lacking IL-17 production. Proc Natl Acad Sci U S A 2009,106(51):21795–21800. doi:10.1073/pnas.0911472106Google Scholar
  34. Funding AT, Johansen C, Kragballe K, Otkjaer K, Jensen UB, Madsen MW, Fjording MS, Finnemann J, Skak-Nielsen T, Paludan SR, Iversen L: Mitogen- and stress-activated protein kinase 1 is activated in lesional psoriatic epidermis and regulates the expression of pro-inflammatory cytokines. J Invest Dermatol 2006,126(8):1784–1791. doi:10.1038/sj.jid.5700252Google Scholar
  35. Funding AT, Johansen C, Kragballe K, Iversen L: Mitogen- and stress-activated protein kinase 2 and cyclic AMP response element binding protein are activated in lesional psoriatic epidermis. J Invest Dermatol 2007,127(8):2012–2019. doi:10.1038/sj.jid.5700821Google Scholar
  36. Fung EY, Smyth DJ, Howson JM, Cooper JD, Walker NM, Stevens H, Wicker LS, Todd JA: Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun 2009,10(2):188–191. doi:10.1038/gene.2008.99Google Scholar
  37. Gaspari AA: Innate and adaptive immunity and the pathophysiology of psoriasis. J Am Acad Dermatol 2006,54(3 Suppl 2):S67-S80. doi:10.1016/j.jaad.2005.10.057Google Scholar
  38. Goldminz AM, Au SC, Kim N, Gottlieb AB, Lizzul PF: NF-kappaB: an essential transcription factor in psoriasis. J Dermatol Sci 2013,69(2):89–94. doi:10.1016/j.jdermsci.2012.11.002Google Scholar
  39. Griffiths CE, Barker JN: Pathogenesis and clinical features of psoriasis. Lancet 2007,370(9583):263–271. doi:10.1016/s0140–6736(07)61128–3Google Scholar
  40. Gudjonsson JE, Johnston A, Sigmundsdottir H, Valdimarsson H: Immunopathogenic mechanisms in psoriasis. Clin Exp Immunol 2004,135(1):1–8.Google Scholar
  41. Gunther C, Carballido-Perrig N, Kaesler S, Carballido JM, Biedermann T: CXCL16 and CXCR6 are upregulated in psoriasis and mediate cutaneous recruitment of human CD8+ T cells. J Invest Dermatol 2012,132(3 Pt 1):626–634. doi:10.1038/jid.2011.371Google Scholar
  42. Hald A, Andres RM, Salskov-Iversen ML, Kjellerup RB, Iversen L, Johansen C: STAT1 expression and activation is increased in lesional psoriatic skin. Br J Dermatol 2013,168(2):302–310. doi:10.1111/bjd.12049Google Scholar
  43. Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z, Xu JH, Cai ZM, Huang W, Zhao GP, Xie HF, Fang H, Lu QJ, Li XP, Pan YF, Deng DQ, Zeng FQ, Ye ZZ, Zhang XY, Wang QW, Hao F, Ma L, Zuo XB, Zhou FS, Du WH, Cheng YL, Yang JQ, Shen SK, Li J, Sheng YJ, et al.: Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 2009,41(11):1234–1237. doi:10.1038/ng.472Google Scholar
  44. Harper EG, Guo C, Rizzo H, Lillis JV, Kurtz SE, Skorcheva I, Purdy D, Fitch E, Iordanov M, Blauvelt A: Th17 cytokines stimulate CCL20 expression in keratinocytes in vitro and in vivo: implications for psoriasis pathogenesis. J Invest Dermatol 2009,129(9):2175–2183. doi:10.1038/jid.2009.65Google Scholar
  45. Henseler T, Christophers E: Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 1985,13(3):450–456.Google Scholar
  46. Huffmeier U, Lascorz J, Traupe H, Bohm B, Schurmeier-Horst F, Stander M, Kelsch R, Baumann C, Kuster W, Burkhardt H, Reis A: Systematic linkage disequilibrium analysis of SLC12A8 at PSORS5 confirms a role in susceptibility to psoriasis vulgaris. J Invest Dermatol 2005,125(5):906–912. doi:10.1111/j.0022–202X.2005.23847.xGoogle Scholar
  47. Huffmeier U, Lascorz J, Becker T, Schurmeier-Horst F, Magener A, Ekici AB, Endele S, Thiel CT, Thoma-Uszynski S, Mossner R, Reich K, Kurrat W, Wienker TF, Traupe H, Reis A: Characterisation of psoriasis susceptibility locus 6 (PSORS6) in patients with early onset psoriasis and evidence for interaction with PSORS1. J Med Genet 2009,46(11):736–744. doi:10.1136/jmg.2008.065029Google Scholar
  48. Huffmeier U, Uebe S, Ekici AB, Bowes J, Giardina E, Korendowych E, Juneblad K, Apel M, McManus R, Ho P, Bruce IN, Ryan AW, Behrens F, Lascorz J, Bohm B, Traupe H, Lohmann J, Gieger C, Wichmann HE, Herold C, Steffens M, Klareskog L, Wienker TF, Fitzgerald O, Alenius GM, McHugh NJ, Novelli G, Burkhardt H, Barton A, Reis A: Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat Genet 2010,42(11):996–999. doi:10.1038/ng.688Google Scholar
  49. Ibrahim G, Waxman R, Helliwell PS: The prevalence of psoriatic arthritis in people with psoriasis. Arthritis Rheum 2009,61(10):1373–1378. doi:10.1002/art.24608Google Scholar
  50. Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF, Joyce CE, Ryan C, Duan S, Helms CA, Liu Y, Chen Y, McBride AA, Hwu WL, Wu JY, Chen YT, Menter A, Goldbach-Mansky R, Lowes MA, Bowcock AM: PSORS2 is due to mutations in CARD14. Am J Hum Genet 2012,90(5):784–795. doi:10.1016/j.ajhg.2012.03.012Google Scholar
  51. Kaminska B, Swiatek-Machado K: Targeting signaling pathways with small molecules to treat autoimmune disorders. Expert Rev Clin Immunol 2008,4(1):93–112. doi:10.1586/1744666x.4.1.93Google Scholar
  52. Krueger JG: The immunologic basis for the treatment of psoriasis with new biologic agents. J Am Acad Dermatol 2002,46(1):1–23. quiz 23–26Google Scholar
  53. Lebwohl M: Psoriasis. Lancet 2003,361(9364):1197–1204. doi:10.1016/s0140–6736(03)12954–6Google Scholar
  54. Lee YA, Ruschendorf F, Windemuth C, Schmitt-Egenolf M, Stadelmann A, Nurnberg G, Stander M, Wienker TF, Reis A, Traupe H: Genomewide scan in german families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13. Am J Hum Genet 2000,67(4):1020–1024. doi:10.1086/303075Google Scholar
  55. Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, Dhodapkar M, Krueger JG: Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med 2004,199(1):125–130. doi:10.1084/jem.20030451Google Scholar
  56. Lew W, Bowcock AM, Krueger JG: Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and ‘Type 1’ inflammatory gene expression. Trends Immunol 2004,25(6):295–305. doi:10.1016/j.it.2004.03.006Google Scholar
  57. Li Y, Cheng H, Zuo XB, Sheng YJ, Zhou FS, Tang XF, Tang HY, Gao JP, Zhang Z, He SM, Lv YM, Zhu KJ, Hu DY, Liang B, Zhu J, Zheng XD, Sun LD, Yang S, Cui Y, Liu JJ, Zhang XJ (2013) Association analyses identifying two common susceptibility loci shared by psoriasis and systemic lupus erythematosus in the Chinese Han population. J Med Genet. doi:10.1136/jmedgenet-2013–101787Google Scholar
  58. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA: Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006,203(10):2271–2279. doi:10.1084/jem.20061308Google Scholar
  59. Liu Y, Krueger JG, Bowcock AM: Psoriasis: genetic associations and immune system changes. Genes Immun 2007,8(1):1–12. doi:10.1038/sj.gene.6364351Google Scholar
  60. Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J, Wise C, Miner A, Malloy MJ, Pullinger CR, Kane JP, Saccone S, Worthington J, Bruce I, Kwok PY, Menter A, Krueger J, Barton A, Saccone NL, Bowcock AM: A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet 2008,4(3):e1000041. doi:10.1371/journal.pgen.1000041Google Scholar
  61. Lizzul PF, Aphale A, Malaviya R, Sun Y, Masud S, Dombrovskiy V, Gottlieb AB: Differential expression of phosphorylated NF-kappaB/RelA in normal and psoriatic epidermis and downregulation of NF-kappaB in response to treatment with etanercept. J Invest Dermatol 2005,124(6):1275–1283. doi:10.1111/j.0022–202X.2005.23735.xGoogle Scholar
  62. Lowes MA, Bowcock AM, Krueger JG: Pathogenesis and therapy of psoriasis. Nature 2007,445(7130):866–873. doi:10.1038/nature05663Google Scholar
  63. Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, Haider AS, Bowman EP, Krueger JG: Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol 2008,128(5):1207–1211. doi:10.1038/sj.jid.5701213Google Scholar
  64. Lu X, Du J, Liang J, Zhu X, Yang Y, Xu J: Transcriptional regulatory network for psoriasis. J Dermatol 2013,40(1):48–53. doi:10.1111/1346–8138.12000Google Scholar
  65. Makredes M, Robinson D Jr, Bala M, Kimball AB: The burden of autoimmune disease: a comparison of prevalence ratios in patients with psoriatic arthritis and psoriasis. J Am Acad Dermatol 2009,61(3):405–410. doi:10.1016/j.jaad.2009.02.015Google Scholar
  66. Manolio TA, Brooks LD, Collins FS: A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008,118(5):1590–1605. doi:10.1172/jci34772Google Scholar
  67. Matthews D, Fry L, Powles A, Weber J, McCarthy M, Fisher E, Davies K, Williamson R: Evidence that a locus for familial psoriasis maps to chromosome 4q. Nat Genet 1996,14(2):231–233. doi:10.1038/ng1096–231Google Scholar
  68. Miossec P, Korn T, Kuchroo VK: Interleukin-17 and type 17 helper T cells. N Engl J Med 2009,361(9):888–898. doi:10.1056/NEJMra0707449Google Scholar
  69. Mischke D, Korge BP, Marenholz I, Volz A, Ziegler A: Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex (“epidermal differentiation complex”) on human chromosome 1q21. J Invest Dermatol 1996,106(5):989–992.Google Scholar
  70. Mueller W, Herrmann B: Cyclosporin A for psoriasis. N Engl J Med 1979,301(10):555. doi:10.1056/nejm197909063011016Google Scholar
  71. Nair RP, Henseler T, Jenisch S, Stuart P, Bichakjian CK, Lenk W, Westphal E, Guo SW, Christophers E, Voorhees JJ, Elder JT: Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan. Hum Mol Genet 1997,6(8):1349–1356.Google Scholar
  72. Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, Jenisch S, Weichenthal M, Abecasis GR, Lim HW, Christophers E, Voorhees JJ, Elder JT: Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am J Hum Genet 2006,78(5):827–851. doi:10.1086/503821Google Scholar
  73. Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, Ruether A, Schreiber S, Weichenthal M, Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok PY, Menter A, Lathrop GM, Wise CA, Begovich AB, Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR: Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 2009,41(2):199–204. doi:10.1038/ng.311Google Scholar
  74. Nakajima K: Critical role of the interleukin-23/T-helper 17 cell axis in the pathogenesis of psoriasis. J Dermatol 2012,39(3):219–224. doi:10.1111/j.1346–8138.2011.01458.xMathSciNetGoogle Scholar
  75. Nestle FO, Turka LA, Nickoloff BJ: Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines. J Clin Invest 1994,94(1):202–209. doi:10.1172/jci117308Google Scholar
  76. Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, Burg G, Liu YJ, Gilliet M: Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005,202(1):135–143. doi:10.1084/jem.20050500Google Scholar
  77. Nestle FO, Kaplan DH, Barker J: Psoriasis. N Engl J Med 2009,361(5):496–509. doi:10.1056/NEJMra0804595Google Scholar
  78. Nickoloff BJ, Nestle FO: Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest 2004,113(12):1664–1675. doi:10.1172/jci22147Google Scholar
  79. Nograles KE, Zaba LC, Guttman-Yassky E, Fuentes-Duculan J, Suarez-Farinas M, Cardinale I, Khatcherian A, Gonzalez J, Pierson KC, White TR, Pensabene C, Coats I, Novitskaya I, Lowes MA, Krueger JG: Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol 2008,159(5):1092–1102. doi:10.1111/j.1365–2133.2008.08769.xGoogle Scholar
  80. Perera GK, Di Meglio P, Nestle FO: Psoriasis. Annu Rev Pathol 2012, 7: 385–422. doi:10.1146/annurev-pathol-011811–132448Google Scholar
  81. Price AL, Zaitlen NA, Reich D, Patterson N: New approaches to population stratification in genome-wide association studies. Nat Rev Genet 2010,11(7):459–463. doi:10.1038/nrg2813Google Scholar
  82. Raychaudhuri S, Sandor C, Stahl EA, Freudenberg J, Lee HS, Jia X, Alfredsson L, Padyukov L, Klareskog L, Worthington J, Siminovitch KA, Bae SC, Plenge RM, Gregersen PK, de Bakker PI: Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 2012,44(3):291–296. doi:10.1038/ng.1076Google Scholar
  83. Samuelsson L, Stiller C, Friberg C, Nilsson C, Inerot A, Wahlstrom J: Association analysis of cystatin A and zinc finger protein 148, two genes located at the psoriasis susceptibility locus PSORS5. J Invest Dermatol 2004,122(6):1399–1400. doi:10.1046/j.0022–202X.2004.12604.xGoogle Scholar
  84. Schlaak JF, Buslau M, Jochum W, Hermann E, Girndt M, Gallati H, Meyer zum Buschenfelde KH, Fleischer B: T cells involved in psoriasis vulgaris belong to the Th1 subset. J Invest Dermatol 1994,102(2):145–149.Google Scholar
  85. Shi X, Jin L, Dang E, Chang T, Feng Z, Liu Y, Wang G: IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. J Invest Dermatol 2011,131(12):2401–2408. doi:10.1038/jid.2011.222Google Scholar
  86. Strange A, Capon F, Spencer CC, Knight J, Weale ME, Allen MH, Barton A, Band G, Bellenguez C, Bergboer JG, Blackwell JM, Bramon E, Bumpstead SJ, Casas JP, Cork MJ, Corvin A, Deloukas P, Dilthey A, Duncanson A, Edkins S, Estivill X, Fitzgerald O, Freeman C, Giardina E, Gray E, Hofer A, Huffmeier U, Hunt SE, Irvine AD, Jankowski J, et al.: A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet 2010,42(11):985–990. doi:10.1038/ng.694Google Scholar
  87. Stuart PE, Nair RP, Ellinghaus E, Ding J, Tejasvi T, Gudjonsson JE, Li Y, Weidinger S, Eberlein B, Gieger C, Wichmann HE, Kunz M, Ike R, Krueger GG, Bowcock AM, Mrowietz U, Lim HW, Voorhees JJ, Abecasis GR, Weichenthal M, Franke A, Rahman P, Gladman DD, Elder JT: Genome-wide association analysis identifies three psoriasis susceptibility loci. Nat Genet 2010,42(11):1000–1004. doi:10.1038/ng.693Google Scholar
  88. Sun LD, Cheng H, Wang ZX, Zhang AP, Wang PG, Xu JH, Zhu QX, Zhou HS, Ellinghaus E, Zhang FR, Pu XM, Yang XQ, Zhang JZ, Xu AE, Wu RN, Xu LM, Peng L, Helms CA, Ren YQ, Zhang C, Zhang SM, Nair RP, Wang HY, Lin GS, Stuart PE, Fan X, Chen G, Tejasvi T, Li P, Zhu J, et al.: Association analyses identify six new psoriasis susceptibility loci in the Chinese population. Nat Genet 2010,42(11):1005–1009. doi:10.1038/ng.690Google Scholar
  89. Tang A, Amagai M, Granger LG, Stanley JR, Udey MC: Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin. Nature 1993,361(6407):82–85. doi:10.1038/361082a0Google Scholar
  90. Tang H, Jin X, Li Y, Jiang H, Tang X, Yang X, Cheng H, Qiu Y, Chen G, Mei J, Zhou F, Wu R, Zuo X, Zhang Y, Zheng X, Cai Q, Yin X, Quan C, Shao H, Cui Y, Tian F, Zhao X, Liu H, Xiao F, Xu F, Han J, Shi D, Zhang A, Zhou C, Li Q, et al. (2013) A large-scale screen for coding variants predisposing to psoriasis. Nat Genet. doi:10.1038/ng.2827Google Scholar
  91. Tobin AM, Kirby B: TNF alpha inhibitors in the treatment of psoriasis and psoriatic arthritis. BioDrugs 2005,19(1):47–57.Google Scholar
  92. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H: Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol 2009,10(8):864–871. doi:10.1038/ni.1770Google Scholar
  93. Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, Ding J, Li Y, Tejasvi T, Gudjonsson JE, Kang HM, Allen MH, McManus R, Novelli G, Samuelsson L, Schalkwijk J, Stahle M, Burden AD, Smith CH, Cork MJ, Estivill X, Bowcock AM, Krueger GG, Weger W, Worthington J, Tazi-Ahnini R, Nestle FO, Hayday A, Hoffmann P, Winkelmann J, et al.: Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet 2012,44(12):1341–1348. doi:10.1038/ng.2467Google Scholar
  94. Uyemura K, Yamamura M, Fivenson DF, Modlin RL, Nickoloff BJ: The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. J Invest Dermatol 1993,101(5):701–705.Google Scholar
  95. Van Belle AB, de Heusch M, Lemaire MM, Hendrickx E, Warnier G, Dunussi-Joannopoulos K, Fouser LA, Renauld JC, Dumoutier L: IL-22 is required for imiquimod-induced psoriasiform skin inflammation in mice. J Immunol 2012,188(1):462–469. doi:10.4049/jimmunol.1102224Google Scholar
  96. Veal CD, Clough RL, Barber RC, Mason S, Tillman D, Ferry B, Jones AB, Ameen M, Balendran N, Powis SH, Burden AD, Barker JN, Trembath RC: Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci. J Med Genet 2001,38(1):7–13.Google Scholar
  97. Veal CD, Capon F, Allen MH, Heath EK, Evans JC, Jones A, Patel S, Burden D, Tillman D, Barker JN, Trembath RC: Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus. Am J Hum Genet 2002,71(3):554–564. doi:10.1086/342289Google Scholar
  98. Vollmer S, Menssen A, Prinz JC: Dominant lesional T cell receptor rearrangements persist in relapsing psoriasis but are absent from nonlesional skin: evidence for a stable antigen-specific pathogenic T cell response in psoriasis vulgaris. J Invest Dermatol 2001,117(5):1296–1301. doi:10.1046/j.0022–202x.2001.01494.xGoogle Scholar
  99. Wang H, Peters T, Kess D, Sindrilaru A, Oreshkova T, Van Rooijen N, Stratis A, Renkl AC, Sunderkotter C, Wlaschek M, Haase I, Scharffetter-Kochanek K: Activated macrophages are essential in a murine model for T cell-mediated chronic psoriasiform skin inflammation. J Clin Invest 2006,116(8):2105–2114. doi:10.1172/jci27180Google Scholar
  100. Wang H, Peters T, Sindrilaru A, Scharffetter-Kochanek K: Key role of macrophages in the pathogenesis of CD18 hypomorphic murine model of psoriasis. J Invest Dermatol 2009,129(5):1100–1114. doi:10.1038/jid.2009.43Google Scholar
  101. Wang H, Syrovets T, Kess D, Buchele B, Hainzl H, Lunov O, Weiss JM, Scharffetter-Kochanek K, Simmet T: Targeting NF-kappa B with a natural triterpenoid alleviates skin inflammation in a mouse model of psoriasis. J Immunol 2009,183(7):4755–4763. doi:10.4049/jimmunol.0900521Google Scholar
  102. Wu JJ, Nguyen TU, Poon KY, Herrinton LJ: The association of psoriasis with autoimmune diseases. J Am Acad Dermatol 2012,67(5):924–930. doi:10.1016/j.jaad.2012.04.039Google Scholar
  103. Yan KL, Huang W, Zhang XJ, Yang S, Chen YM, Xiao FL, Fan X, Gao M, Cui Y, Zhang GL, Sun LD, Wang PG, Chen JJ, Li W, Chen ZH, Wang ZM, Wang DZ, Zhang KY, Liu JJ: Follow-up analysis of PSORS9 in 151 Chinese families confirmed the linkage to 4q31–32 and refined the evidence to the families of early-onset psoriasis. J Invest Dermatol 2007,127(2):312–318. doi:10.1038/sj.jid.5700506Google Scholar
  104. Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, Abello MV, Novitskaya I, Pierson KC, Gonzalez J, Krueger JG, Lowes MA: Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Invest Dermatol 2009,129(1):79–88. doi:10.1038/jid.2008.194Google Scholar
  105. Zhang XJ, Zhang AP, Yang S, Gao M, Wei SC, He PP, Wang HY, Song YX, Cui Y, Chen JJ: Association of HLA class I alleles with psoriasis vulgaris in southeastern Chinese Hans. J Dermatol Sci 2003,33(1):1–6.Google Scholar
  106. Zhang XJ, Yan KL, Wang ZM, Yang S, Zhang GL, Fan X, Xiao FL, Gao M, Cui Y, Wang PG, Sun LD, Zhang KY, Wang B, Wang DZ, Xu SJ, Huang W, Liu JJ: Polymorphisms in interleukin-15 gene on chromosome 4q31.2 are associated with psoriasis vulgaris in Chinese population. J Invest Dermatol 2007,127(11):2544–2551. doi:10.1038/sj.jid.5700896Google Scholar
  107. Zhang XJ, Huang W, Yang S, Sun LD, Zhang FY, Zhu QX, Zhang FR, Zhang C, Du WH, Pu XM, Li H, Xiao FL, Wang ZX, Cui Y, Hao F, Zheng J, Yang XQ, Cheng H, He CD, Liu XM, Xu LM, Zheng HF, Zhang SM, Zhang JZ, Wang HY, Cheng YL, Ji BH, Fang QY, Li YZ, Zhou FS, et al.: Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat Genet 2009,41(2):205–210. doi:10.1038/ng.310Google Scholar
  108. Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, Ouyang W: Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007,445(7128):648–651. doi:10.1038/nature05505Google Scholar

Copyright

© Sun and Zhang; licensee Springer. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

Advertisement