Psoriasis: Genetic Associations and Immune System Changes

REVIEW Psoriasis: genetic associations and immune system changes

Y Liu1, JG Krueger2 and AM Bowcock1,3 1Department of Genetics, Washington University School of Medicine, St Louis, MO, USA; 2Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY, USA and 3Departments of Pediatrics and Medicine, Washington University School of Medicine, St Louis, MO, USA

Psoriasis is a common inflammatory skin disease characterized by infiltration of inflammatory cells into the epidermis and altered keratinocyte differentiation. Psoriasis is currently thought of as a T-cell mediated ‘Type-1’ autoimmune disease. Gene expression changes in psoriasis lesions have been well documented, and strongly support an important role for tumor necrosis factor and interferon gamma signal pathways in its pathogenesis. The strongest genetic determinant of psoriasis identified to date lies within the class I region of the multiple histocompatibility locus antigen cluster, although its low penetrance implicates a requirement for other genetic risk factors. Multiple genome-wide linkage and an increasing number of association studies have been carried out, leading to multiple linkage peaks, and the identification of potential low risk variants. A number of these variants lie within genes encoding components of the immune system. However, the functional relationships between predisposing genetic variation is unclear, and presumably involves genetic susceptibility factors affecting both immune cell activation and keratinocyte differentiation. The interaction of environmental trigger factors with genetic effects is also not understood, but provide further evidence for the complex basis of this disease. Genes and Immunity (2007) 8, 1–12. doi:10.1038/sj.gene.6364351; published online 9 November 2006

Keywords: psoriasis; genetics; association; immunology

Introduction/historical perspective individuals, producing a pattern of growth recognized as psoriasis. Psoriasis is a common chronic inflammatory skin disease The view of psoriasis as a T-cell mediated ‘auto- that affects 2–3% of the Caucasian population. It immune’ or inflammatory disease has evolved most frequently develops in early adulthood in individuals directly from clinical studies of disease response to a between 15 and 30 years old, although individuals of all range of immune antagonists. However, this view of ages can be affected. The disease is characterized by immune-mediated pathogenesis is also strongly sup- thickened, scaly skin patches or psoriatic plaques, caused ported from study of human skin xenografts in mice and by abnormal keratinocyte proliferation and infiltration by the identification of clonal populations of T cells of inflammatory cells into the dermis and epidermis. within intact skin lesions. Approximately 10–30% of patients with psoriasis also develop psoriasis arthritis. Once psoriasis appears, it is usually a life-long disease. Spontaneous disease im- provement is uncommon and more severely affected individuals often have progressively increasing amounts Triggers of the skin surface affected. Psoriasis can be triggered by an array of factors that One theory for the development of psoriasis is that T includes physical injury to the skin (the ‘Koebner’ cells and dendritic cells (DCs) elaborate inflammatory response), administration of interferons (IFN) or other cytokines and chemokines to create an environment in inflammation-inducing stimuli, rapid withdrawl of im- the skin that stimulates proliferation of resident kerati- munosuppressive drugs like corticosteroids and (sys- nocytes and endothelial cells in genetically susceptible temic) infections with streptococcus or other bacteria.1,2 A recent report suggests that psoriasis can be induced by a chemical agonist that activates toll-like receptor 7. This may be via IFN-a secreted by dermal DCs.3 Although Correspondence: Dr AM Bowcock, Department of Genetics, these are diverse stimuli, all might be viewed as trigger Washington University School of Medicine, 4566 Scott Avenue, factors that can activate cellular immunity. This could be St Louis, MO 63110, USA. E-mail: [email protected] through innate or acquired pathways and would serve as Received 22 September 2006; accepted 27 September 2006; inducers of a chronically perpetuated immune response published online 9 November 2006 in the skin of predisposed individuals. Psoriasis: genetic associations YLiuet al 2 Regenerative keratinocyte differentiation and is associated with the induction of keratins 6 and 16 in psoriasis in suprabasal keratinocytes. The physically expanded proliferative compartment is Figure 1a illustrates some of the major differences accompanied by suprabasal expression of insulin-like between normal and involved psoriatic skin. The overall growth factor-1 receptors and b1-integrins.6,7 Corneo- set of cellular and molecular changes in chronic psoriasis cytes do form with corneodesmosomes and a cornified plaques is complex and large-scale genomic analyses envelope, but neutral lipids are not secreted in a normal have identified altered expression of 41300 gene manner into the extracellular space from Odland products in involved skin of lesions compared to bodies.8,9 The result of incomplete differentiation/para- unaffected (non-lesional) skin of the same individuals.4 keratosis is that the stratum corneum barrier is not Transcripts with the highest steady-state levels that are formed correctly in psoriasis plaques. The consequences upregulated in involved skin are expressed by the are a defective water/vapor barrier and the shedding of keratinocyte. Some affect its innate immune system, strateum corneum fragments in large sheets of scales/ including the upregulation of beta defensin. Expression flakes. levels of messenger RNAs (mRNAs) transcribed by T Intercellular cell adhesion molecule (ICAM)-1, CD40 cells and DCs are at far lower levels owing to the and human leukocyte antigen dimensional reconstruc- overwhelming number of keratinocytes in lesions. tion (HLA-DR) are expressed on the surface of some The transit from a basal keratinocyte to a desquamated basal/suprabasal keratinocytes in psoriasis lesions.10 cell takes 4–6 weeks in normal skin. In psoriasis this is ICAM-1 is a general ligand for b2-integrins expressed dramatically shortened, occurring in only a few days. on T-cells, DCs and neutrophils and may enable intra- Many cellular products normally produced in the epidermal trafficking of leukocytes. CD40 and HLA-DR granular layer become expressed in upper spinous molecules potentially interact with cognate receptors on keratinocytes in the psoriatic lesion. These alterations T cells and could potentially deliver activation signals. are part of an accelerated differentiation also seen in Keratinocytes in psoriasis lesions also synthesize numer- regenerative maturation.5 In normal skin this is a ous proteins that can serve as chemotactic factors for the program triggered by wounding of the skin that rapidly array of leukocytes found in lesional epidermis.4 initiates transcription of new genes in keratinocytes. This Activated keratinocytes mediate angiogenesis through accelerates proliferation of basal keratinocytes, as well as increased synthesis of vascular endothelial growth factor the differentiation of spinous and granular keratinocytes (VEGF), platelet-derived growth factor (PDGF) and other

Figure 1 (a) Major differences between normal and psoriatic epidermis with respect to structure and gene expression. (b) Localization of immune cells in psoriatic lesions. Some of the immune related genes expressed by infiltrating T cells are: IL-1, IL-2, IL-2R, IL-2 inducible T-cell kinase, TCRB, TNF, IFN-g, IL-17, VEGF, GM-CSF, LYN; dendritic cells in the epidermis express CD11c, DECTIN, IL-1b, IL-12, IL-23, TNF, IFN-a, MDC/CCL22, PARC/CCL18, Bonzo receptor ligand/CXCL16, MIP-3b/CCL19. Keratinocytes express IL-1b, IL-6, IL-8, Ltb, TNFIL-18, TGFa, amphiregulin, VEGF, PDGF, ECGF, Groa/MGSA, MCP-1/CCL2, MIP3a/CCL20, MIG/CXCL9, IP-10/CXCL10, I-TAC/CXCL11, RANTES/CCL5, ENA-78/CXCL5 and CTACK/CCL27. Each of these has an effect on other cell types in the skin, and on endothelial and stromal cells.

Genes and Immunity Psoriasis: genetic associations YLiuet al 3 endothelial cell mitogens.11–13 A unique link between related to cytokine secretion and migration through the regenerative hyperplasia and inflammation may be epidermis, they also synthesize the cytotoxic granule provided by synthesis of S100 proteins (A7, A8, A9, components Tia-1, granzyme B and perforin.22,23 A12) that are encoded by the epidermal differentiation Normal skin, as well as non-lesional skin of psoriasis complex (EDC) genes.14 patients, contains resident populations of immature DCs In psoriasis lesions, there is tremendous growth of the in the epidermis and dermis. However, psoriasis lesions most superficial capillaries. Highly elongated and contain several alterations in DCs. First, there is a tortuous vessels become very prominent in the elongated marked increase in the number of myeloid DCs, marked dermal papillae. Endothelial cells in these elongated by the integrin CD11c, in the dermis. Moreover, CD11c þ vessels strongly express ICAM-1, the peripheral lymph DCs may be the largest subset of infiltrating leukocytes node addressin, and a variety of other adhesion in psoriasis lesions.24 CD11c þ DCs express high levels of molecules that are normally restricted to vessels in TNF and have strongly upregulated expression of lymph nodes or to secondary lymphoid tissues. inducible nitric oxide synthase (iNOS), an enzyme which Keratinocytes in psoriasis plaques express some synthesizes nitric oxide. Hence this group of myeloid immune-related molecules that are not normally asso- DCs may be the human equivalent of TNF and iNOS- ciated with wound-related regenerative hyperplasia. producing DCs (TIP-DCs), a newly discovered DC subset These immune-related molecules may be induced in with direct inflammatory/effector functions.25 Whereas keratinocytes following exposure to high concentrations myeloid DCs are confined to the dermis in normal skin, of tumor necrosis factor (TNF) and g-IFN produced in TIP-DCs invade into the epidermis in psoriasis lesions. psoriatic lesions,15,16 and may be specifically upregulated Myeloid DCs may trigger epidermal hyperplasia directly in genetically predisposed individuals. by secretion of IL-20, a cytokine that not only stimulates keratinocyte proliferation, but which also induces key inflammatory gene products in keratinocytes.26 Second, Immune cells in psoriatic lesions DCs in psoriasis lesions have more capacity to stimulate T-cell proliferation compared to DCs in normal skin.27 Immune cells that infiltrate into psoriatic skin are This increased stimulatory activity correlates with diagrammed in Figure 1b. In normal skin, a small upregulation of HLA-DR,CD40, CD86 and other surface number of T cells can be found in the dermis, but no T molecules which are expressed at higher levels on cells are located in the epidermis. Likewise, in normal mature or activated DCs. Markers of mature DCs, skin, a relatively small number of myeloid (CD11c þ ) including DC-LAMP and CD83, are expressed on many DCs are located in dermis, whereas Langerhans cells are DCs in psoriasis lesions, whereas very few DCs in found mainly in the epidermis. In psoriasis lesions, there normal skin have these markers. Activated myeloid DCs are marked increases in the number of T cells and may also produce IL-23;28 this is a potent T-cell activating CD11c þ DCs. T cells, especially CD8 þ T cells, migrate cytokine that is discussed further below. Mature DCs into all layers of the epidermis in psoriasis lesions. form aggregates or clusters with T cells in the dermis of CD11c þ DCs also infiltrate the epidermis of psoriasis psoriasis lesions. These mixed aggregates, which consist lesions, but they are confined to the lower cell layers of of many hundreds of cells, may perpetuate T-cell the epidermis. Langerhans cells continue to be present activation in psoriasis lesions, and conversely, products in psoriatic epidermis, but they appear to migrate into of activated T cells (secreted cytokines or induced surface the upper spinous zone, in contrast to normal skin molecules such as CD40L) may react with DCs in these where the distribution is relatively uniform. Neutrophils regions to induce/sustain mature populations of DCs. accumulate in small aggregates in the cornified epi- Chemokines that organize lymphoid structures in lymph dermis. nodes are, surprisingly, highly upregulated in psoriatic T cells are thought to be critical pathogenic triggers skin lesions and may thus create secondary lymphoid in psoriasis where epidermal CD8 þ and dermal CD4 þ structures in the skin. A third feature of DCs in psoriasis T cells are highly activated and express CD25 (the lesions is the marked accumulation of plasmacytoid interleukin (IL-2) receptor a-subunit).17 Both of these (CD11cÀCD123 þ ) DCs.29 This group of DCs, which T-cell subsets have type-1 effector functions and can be secrete high levels of IFN-a upon activation, have been 18 classified as Tc1 and Th1 populations, respectively. TNF proposed as a critical early initiator of cellular inflamma- and IFN-g, are synthesized by these activated T cells and tion in the formation of psoriasis lesions. are key cytokines for activating keratinocytes. More than Two other types of T cells may also be important in 100 genes are induced by short-term exposure of psoriasis: IL-17 producing cells and natural killer (NK)-T keratinocytes to these cytokines.15,16 cells. In mice, IL-23 induces IL-17-producing T-cells 30 The CD8 þ subset of T cells that diffusely infiltrate the which are effectors distinct from Th1 cells. Many epidermis of psoriasis lesions are mainly LFA1hi CD8 þ CD4 þ and CD8 þ T-cell clones isolated from psoriasis T cells. Most T cells in psoriasis lesions are memory cells lesions produce IL-17.31 IL-23 is produced at elevated (CD45Ro þ or CD45RAÀ)19,20 and many specialized levels in psoriasis lesions,28 so it might serve as a subsets are represented in this infiltrate. A significant stimulus for in situ differentiation of IL-17 þ effectors. fraction of T cells in lesions express the epithelial homing IL-17 has been shown to synergize with TNF and IFN-g 21 integrin aEb7. They also express the chemokine receptor for induction of IL-6, IL-8 and other inflammatory CXCR3, which allows them to migrate towards CXCL9/ products in keratinocytes.31 MIG, CXCL10/IP-10 and CXCL11/I-TAC. These chemo- Excessive transcription of genes that lead to DC kines are synthesized at increased levels by keratinocytes activation or those that restrict the migration of mature in psoriasis lesions. Although the pathogenic action of DCs from peripheral tissues may be central to sustaining

CD8 þ (Tc1) T cells in psoriasis lesions may be mostly T-cell activation. Alternatively, some psoriasis suscepti-

Genes and Immunity Psoriasis: genetic associations YLiuet al 4 bility genes may affect deletion of self-reactive T cells, the T cells), with downstream activation/amplification induction of regulatory T cells by changing signal of inflammation through a group of IFN-induced transduction through the T-cell receptor (TCR) or co- gene products that constitute B5% of the psoriasis stimulatory pathways, may trigger an inappropriate transcriptome.33 In this model, TNF, IFN and IL-17 innate immune response or may alter the threshold for are all likely to be important T-cell derived cytokines immune cell activation or the rate of immune synapse that stimulate these ‘Type-1’ pathway genes. End- formation/dissolution.32 stage products of the Type-1 pathway include a Previously, we proposed a relatively simple ‘Type-1’ number of chemokines that probably stimulate on-going pathway in psoriasis that links expression of IL-23 leukocyte recruitment into skin lesions on a chronic to activation of Type-1 T cells (and potentially IL-17 þ basis.

Figure 2 Network model of inflammatory pathways commonly upregulated in psoriasis. Ingenuity Pathways Analysis (Ingenuity Systems, www.ingenuity.com) was used to identify relevant biological networks. Shaded nodes represent upregulated genes in psoriasis identified by microarray analysis or genes thought to be primary biological triggers (e.g. TNF, IFNG). The meanings of node shape are indicated. Solid lines imply direct relationships between proteins; dotted lines imply indirect interactions. Relationships are primarily due to co-expression, but can also include phosphorylation/dephosphorylation, proteolysis, activation/deactivation, transcription, binding, inhibition, biochemical modification.

Genes and Immunity Psoriasis: genetic associations YLiuet al 5 The ‘Type-1’ pathway model is probably a gross over- Genetics of psoriasis simplification of complex interactions of inflammatory molecules in psoriasis lesions, especially as 4100 At this point, complex gene expression changes in inflammatory gene products are upregulated in psoriasis psoriasis are well described, but functional relationships lesions. It is likely that products of genes which are between the predisposing genetic factors and the cellular upregulated in psoriasis interact in complex circuits to elements of pathogenic immunity are not well worked regulate activation of skin-resident cells, infiltrating out. It is expected that knowledge of predisposing leukocytes and inflammatory pathways. One example variants in susceptible individuals and exposure to of interacting pathways is shown in Figure 2. This environmental triggers will eventually explain the pathway, although shown as interacting genomic ele- numerous changes that exist in psoriatic skin. What is ments, links activation or accumulation of several cell becoming apparent is that a number of susceptibility types in psoriasis lesions. For example, the chemokines factors in the population lead to subtle alterations in CCL20/MIP-3a, CCL19/MIP-3b, CCL21/6Ckine and activity of components of the immune system. Psoriasis CXCL12/SDF-1 are key attractors of DCs that we have susceptibility locus 4 (PSORS4) in the EDC on chromo- termed TIP-DCs (see above).4,32,33 In addition, cytokines some 1, for instance, may specifically alter keratinocyte differentiation, but involvement of other loci remains like IL-12 and IL-23 that stimulate Th1 T-cells (defined by unclear. expression of g-IFN or the IFNG gene) and/or Th17 T- cells (defined by expression of IL-17 gene/cytokine) are The existence of a genetic contribution of psoriasis is produced by DCs in psoriasis lesions.28 Note upregula- well accepted. Previous twin studies in psoriasis report tion of the IL-23R, which may indicate increased that concordance of the disease in monozygotic twins is sensitivity to IL-23 cytokine production in psoriasis. much higher than in dizygotic twins, being approxi- Disease-relevant T cells may be drawn into skin mately 72 and 15–23%, respectively, for northern lesions through increased expression of chemokines European individuals. A similar trend is also observed like CCL27/CTACK, CXCL9/MIG, CXCL10/IP-10, in Australian individuals. These results indicate that CXCL11/I-TAC and several other chemokines that are genetic components play a role in predisposition to the disease, and it is estimated that the heritability for expressed in this network. Neutrophils may be attracted 39 into skin lesions by the chemokines IL-8 and CXCL1/ psoriasis is between 60 and 90%. Currently, few genes Gro-a.4,32,33 At least three products of this network, for psoriasis have been conclusively identified, although a a genome wide linkage scans have revealed 20 potential IL-1A/IL-1 , TGFA/TGF- and IL-19 can serve as 40 keratinocyte mitogens, whereas the cytokines IFNG, loci over the past 12 years. TNF and IL-17 act on keratinocytes as inducers of As with all complex diseases, linkages and associa- chemokines, as well as many other genes that become tions with psoriasis have not always been replicated in upregulated in psoriasis, including defensin genes other cohorts. This can be due to low effect size of (DEFB4 and DEFB103A genes).34 STAT1, shown in the individual genetic variation, ascertainment bias, gene– network, is among the most upregulated transcription environment interactions and other confounding factors. factors in psoriasis and may account for a very high Among the reported psoriasis susceptible loci, the locus fraction of upregulated gene products.33 Therapeutics in the major histocompatibility complex (MHC) on which reverse psoriasis in a considerable fraction of chromosome 6p21, known as PSORS1, is the only one treated patients (infliximab, etanercept, adalimumab and that has been consistently identified in genome-wide CNTO-1275) target key cytokines that drive expression of scans, accounting for one-third to one-half of the genetic key elements of this network.35,36 liability to psoriasis.

PSORS1 Uninvolved skin of patients The strong association of HLA-Cw6 allele in this locus with psoriasis was first reported in the Finnish popula- Background skin of psoriasis patients is very similar to tion over 26 years ago.41 However, the exact location of normal skin until a psoriasis lesion is triggered. The PSORS1 gene remains controversial owing to extensive earliest recognizable change in eruptive lesions is the linkage disequilibrium across this region. Two genes accumulation of mononuclear leukocytes (T cells and lying within this interval have been intensively studied monocytes/DCs) around dermal blood vessels, without with respect to their role in psoriasis susceptibility. One any epidermal reaction.37 It is not known what triggers is HCR (helix coiled coil rod homolog);42 the other is these cell accumulations but it could be in response to corneodesmosin (CDSN/S). CDSN is expressed in term- some antigen-based trigger, or to a different innate inally differentiated keratinocytes and in the inner root stimulation, leading to upregulation of chemokines and sheath of hair follicles.43–45 It localizes to the modified adhesion molecules. desmosomes of keratinocytes in the stratum granulosum Very little molecular information is available about this and stratum corneum. The serine and glycine-rich stage of disease evolution. However, background (non- terminal domains of CDSN that are essential for cell lesional) skin of psoriasis patients undergoing a psoriatic adhesion are sequentially cleaved during skin desqua- ‘flare’ contains more T cells than found in skin of normal mation.46,47 Apart from the skin, CDSN mRNA is only controls. Several inflammatory genes (CD4, CD103/aE- detected significantly in the placenta and in the integrin, CD11c and BRAK/CXCL14) are expressed at thymus.48 higher levels compared to normal skin.4 CXCL14 is a Several recent studies inducate that PSORS1 is likely to monocyte-selective chemokine, which may explain in- lie very close to HLA-C, and distinct from the region creased expression of CD11c (selectively expressed by harboring CDSN and HCR. Two single-nucleotide poly- myeloid cells).38 morphisms (SNPs) (SNP n.9 and SNP n.7), lying B5.7

Genes and Immunity Psoriasis: genetic associations YLiuet al 6 and B10 kb, respectively upstream from the start site of presentation of psoriasis. For example, clinical manifes- HLA-C exhibit stronger association with psoriasis than tations included not only both plaque psoriasis and any other SNP in the region.49 A study from our group erythrodermic psoriasis, but also very mild skin lesions looking at both SNPs and classical HLA alleles revealed and histopathologic findings reminiscent of pityriasis that haplotypes harboring HLACw*0602 and HLA- rubra pilaris. What may be noteworthy is that ZNF750 is Cw*1203 were over-transmitted to affecteds, suggesting normally expressed in keratinocytes but not in fibro- that a variant or combination of variants exclusive to blasts and is hardly detectable in CDA lymphocytes. these haplotypes were predisposing.50 Interestingly, one of these variants leads to acquisition of an additional site Proximal PSORS2 locus for the transcription factor RUNX, within intron 7. This A five-marker variant in a region on chromosome 17q25 is highly correlated with the SNP n.9 and SNP n.7 harboring SLC9A3R1 and NAT9 was identified with polymorphisms (r2 ¼ 1). association mapping.58 Both genes encode proteins that A recent study comparing risk haplotypes from play a role in negatively regulating immune cell unrelated individuals as well as families with early- activation. This role seems to be more pronounced when onset psoriasis revealed that HLA-Cw6 may be ‘the’ risk the non-psoriasis-associated allele is present. One psor- allele for psoriasis in this locus.51 Given the confounding iasis-associated allele from this five marker haplotype discrepancies in results from different groups and the leads to loss of a putative site for the RUNX family of importance of the identification of PSORS1, a psoriasis transcription factors. This is of interest as RUNX1 and consortium has been established to investigate PSORS1 RUNX3 play a major role in hematopoietic development across a combined set of patient/family cohorts. This and thymic selection (see below). Moreover, alterations exploits knowledge from the HapMap project that has of RUNX binding sites have also been reported as facilitated the identification of tagging SNPS and susceptiblity variants for systemic lupus erythematosus haplotypes across the region.52 and rheumatoid arthritis.59,60 In all cases these variants Although PSORS1 is the only locus for psoriasis lie in intronic or in intragenic regions. It is currently not identified in all genetic studies to-date, its estimated clear if it is RUNX1, RUNX2 or RUNX3 that is binding to penetrance is less than 15%, indicating that other the altered sites in auto-immune diseases, as all have genetic/environmental factors may also contribute to been reported to recognize the same consensus sequence the liability of the disease. The known remaining TGt/cGGT. RUNX proteins are key regulators of lineage- potential loci are discussed below. Some may confer specific gene expression. RUNX1 is a master-regulator effects independent of PSORS1, others may be PSORS1 of the hematopoietic system. RUNX2 is required for modifiers. osteogenesis and RUNX3 controls neurogenesis.61 It is also worth noting, that HLA class I alleles rarely RUNX1 is also frequently disrupted in acute myelocytic show evidence for linkage to psoriasis in large multiply leukemia via translocation or point mutation.62 A affected families. There are two possible explanations for RUNX3 knockout mouse has been described with this. Some large families may harbor other loci, and be eosinophilic airway inflammation.63 They also sponta- truly PSORS1 negative (e.g. a locus on chromosome 18p neously develop an inflammatory bowel disease that is identified with linkage analyses in the Finnish popula- characterized by leukocyte infiltration, mucosal hyper- tion).53 In other large families, multiple affected may plasia, formation of lymphoid clusters and increased harbor HLA-Cw*0602 on multiple haplotypes.50 production of immunoglobulin A.64 RUNX3-deficient cytotoxic T cells, but not helper T cells, have defective PSORS2 response to antigen. The epidermis of RUNX3 knockout PSORS2 on chromosome 17q25 was the first identified mice also lacks epidermal Langerhans cells but not non-MHC locus that confers susceptibility to psoriasis. dendritic epidermal cells. RUNX3 also plays a role in Our group initially identified this region by genome- development of gamma delta T cells (found in skin). It is wide linkage scan on eight Caucasian affected families, detected mainly in the CD4ÀCD8 þ subset of thymo- among which PS1 family (19 affected and 12 unaffected cytes, and may play a role in the development and members) showed strong linkage to D17S784 marker maturation of these cells.65 These findings provide with a maximal two point logarithm of the odds (LOD) important evidence for a role for RUNX3 pathways in score of 5.33, with high penetrance.54 Evidence from a tolerance or inflammation. From the perspective of recent linkage study on a single large-pedigree in Taiwan complex autoimmune diseases it suggests that the replicated our linkage findings, mapping this psoriasis altered RUNX sites (generally polymorphisms) in differ- susceptibility locus to the distal end of chromosome ent genes encoded by specific inflammatory cells or in 17q.55,56 In this case, a LOD score of 7.67 at y ¼ 0.01 was cells of target tissues may increase the risk of auto- obtained with D17S784, and as with the former study, no immune disease by altering their normal regulation (e.g. recombinants were detected with the most distal locus, lowering the threshold for activation of immune genes). D17S928 that lies B800 kb from the 17q terminus. A third independent PSORS2-linked Israeli Jewish Moroccan RAPTOR family was also recently identified.57 The disease in this A second more distal locus mapping distal to D17S784 family was also linked to D17S928 (maximum multipoint and within the region of linkage seen in the three large LOD score of 8.79 at y ¼ 0) and segregates with a families described above harbors RAPTOR (Regulatory frameshift mutation in ZNF750 (FLJ13841), which en- associated protein of mTOR). Intronic SNPs have been codes a putative C2H2 zinc-finger protein. The general shown to be associated with psoriasis in our set of US applicability of this allelic effect of ZNF750 to poriasis families and an independent set of families from the susceptibility is not clear at this point. It is conceivable UK.58,66 The significance of this association is currently that the family studied was somehow unique in its not understood.

Genes and Immunity Psoriasis: genetic associations YLiuet al 7 Table 1 Genes/variants associated with psoriasis in at least one study

Gene Gene title Chromosome band Polymorphism(s) location References

IL-10 Interleukin 10 1q31–q32 Promoter (microsatellite) 98 IL-12B/p40 subunit Interleukin 12B 5q31.1–q33.1 Upstream gene, 30-UTR (SNP) 90,91 IL-19/IL-20/IL-24 Interleukin 19/interleukin 20/ 1q32 Haplotype 96 interleukin 24 IL-23R Interleukin 23 receptor precursor 1p31.3 Missense alteration 91 IRF2 Interferon regulatory factor 2 4q35.1 Non-coding SNP 77 MGST2 Microsomal glutathione 4q28.3 Gene disruption/non-coding SNP 78, Unpublished, S-transferase 2 Bowcock and Helms PTPN22 Protein tyrosine phosphatase, 1p13.3–p13.1 Two associated haplotypes in 84 non-receptor type 22 German psoriatics RAPTOR Regulatory associated protein of 17q25 Non-coding SNPs 58,66 mTOR SLC12A8 Solute carrier family 12 member 3q21 Non-coding haplotype in Swedish 67 A8 families SLC9A3R1/NAT9 Solute carrier family 9 (sodium/ 17q25.1 Non-coding SNPs/haplotype 58 hydrogen exchanger), member 3 regulator 1 SUMO4 Small ubiquitin-like modifier 4 6q25.1 M55V Unpublished, Bowcock protein and Helms TNF Tumor necrosis factor 6p21.3 Promotor SNPs 87,88

Abbreviations: IL, interleukin; mTOR, mammalian target of rapamycin; RAPTOR, regulatory associated protein of mTOR; SNP, single- nucleotide polymorphism; TNF, tumor necrosis factor; UTR, untranslated region.

Variants other than those from PSORS1 and reported findings implicate the same genetic defects, potentially to be associated with psoriasis in at least one study are keratinocyte derived, in both diseases. However, in described in Table 1. several recently described studies, the defects have been shown to be different. For example, two loss-of-function PSORS3 mutations (R501X and 2282derl4) in the filaggrin gene SLC12A8, (solute carrier family 12 (bumetanide-sensitive that cause ichthyosis vulgaris, one of the most common Na-K-Cl cotransporters), member 8) was the first gene inherited skin disorders of keratinization, have been proposed to be associated with psoriasis susceptibility.67 reported to be strong predisposing factors for AD in the This gene is a member of the cation-chloride-coupled heterozygous state. These mutations are found in B9% cotransporter gene family,68 although the substances it of Europeans, yet in 44–76% of cases.74 In the case of transports are unknown. A five-marker haplotype from chromosome 17q25, associations between the SLC9A3R1/ the 30 end of the SLC12A8 gene was associated with NAT9 psoriasis-associated variants, are not seen in atopic psoriasis in Swedish families, in keeping with the fact dermatitis.75 that some susceptibility variants of complex traits affect gene regulation rather than changing coding sequence. Association of SLC12A8 and psoriasis has not been PSORS9 replicated in other populations until recently when Chromosome 4q28–q31 has continued to be of interest examination of SNPs and haplotypes in a set of cases/ with respect to psoriasis because although the effects of controls and trios from Germany found association in the this locus are relatively weak, it is detected consistently cases/controls, but not trios.69 Association in cases but in many genome-wide scans of families from both not trios in general creates concern about underlying Europe and the Han Chinese population.76 This suggests population stratification in the case/control population. that the susceptibility variant arose before the divergence of these two populations (B70 000 years ago). An PSORS4: the EDC on chromosome 1q21 alternative explanation is that the variant has arisen This harbors a number of genes involved in epidermal independently in the two populations. Different genetic differentiation. They form a cluster of genes on chromo- analyses point to the existence of several susceptibility some 1q21 and span over 2 Mb. Linkage to chromosome genes in this region of the genome, and chromosome 4q 1q21 was first described in Italian families,70 although may harbor several loci for psoriasis susceptibility. This suggestive evidence for linkage was seen at the same region harbors over 300 genes, but there are some time in our cohort of multiplex families from the US, and compelling candidate genes including IL-15, and IFN was replicated in our cohort of affected sibship pairs.71 regulatory factor 2 (IRF-2). The latter is an important Recent unpublished results suggest that PSORS4 lies candidate as it is involved in negative regulation of IFN-g within a region harboring SPRR and LEP genes. Hence, signaling. Moreover, mice deficient in IRF-2 display PSORS4 is likely to be involved in terminal differentia- psoriasis-like skin abnormalities. Weak association of tion of keratinocytes. There is also evidence for interac- IRF-2 variants with psoriasis has been reported tion between PSORS1 and PSORS4.72 (PSORS3).77 It is not clear if this is because the true PSORS4 is one of four loci also shown to be linked variant has not been detected in this, or a nearby gene, or to atopic dermatitis (1q21, 3q21, 17q25 and 20p).73 These if the association is spurious.

Genes and Immunity Psoriasis: genetic associations YLiuet al 8 Recently, a psoriasis patient with a balanced transloca- including the stress response and keratinocyte proliferation involving chromosome 4q was reported. This tion and differentiation. This is in agreement with recent disrupts the MGST2 (microsomal glutathione S-transfer- observations that activation of NF-kB plays a significant ase 2) gene which is involved in catalyzing the conjuga- role in the pathogenesis of psoriasis where basal level of tion of leukotriene C4 (LTC4), and the conversion of LTA4 constitutive active phosphorylated NF-kB/RelA is de- into LTC4.55 It is hypothesized that the elevated level of tected in uninvolved epidermis from psoriasis patients, LTB4, found in psoriatic lesions could be due to an in contrast to normal epidermis where active nuclear NF- accumulation of LTA4. We examined association of kB is not detected. Active phosphorylated NF-kB/RelA MGST2 tag SNPs with psoriasis and did find some is also upregulated in the epidermis from psoriatic evidence for association (P ¼ 0.004) with an intronic SNP plaque.86 Hence, a role for SUMO4 in psoriasis is rs2602238 (Helms and Bowcock, unpublished results). plausible. This suggests that MGST2 could be a risk factor for this TNF-a: Many lines of evidence point to an important disease. Interestingly a novel non-synonymous mutation role for TNF in psoriasis, and many genes upregulated in in MGST2 has been seen in one Chinese family with involved skin, are regulated, at least in part, by this psoriasis,78 however, no association with MGST2 SNPs cytokine (see above). TNF increases the synthesis of was seen in an independent study investigating a cohort proinflammatory cytokines and leads to the activation of of Chinese patients.79 multiple signaling pathways, including NF-kB. Poly- morphisms in the promoter of TNF, regulating its level, Overlap of psoriasis loci with other auto-immune and have been of interest for many years and some evidence inflammatory diseases has been provided for association with psoriasis.87,88 Psoriasis is an ‘inflammatory’ disease that strongly However, the gene encoding TNF-a lies in the MHC depends on activation of the cellular immune system. It region, and exhibits association with HLA class I alleles is not known if it is officially an autoimmune disease such as HLA-C. Hence, associations with TNF-a poly- with reactivity to self-antigens. Neverless, there is over- morphisms with psoriasis could be due to its proximity lap with a number of other ‘autoimmune’ human with HLA-C. The existence of an independent effect of diseases like inflammatory bowel disease, Crohns, TNF-a variants in psoriasis susceptibility or severity, diabetes and multiple sclerosis. This overlap is seen both independent of HLA-C need to be formally investigated. at the level of altered biochemical pathways, and with IL-12B/IL-23R: Two studies have considered IL-12B as respect to the locations of loci mapped by linkage a candidate psoriasis gene. One excluded association analysis.73,80 with a promoter polymorphism.89 The second identified Genes that have been shown to be shared nearly a polymorphism in the 30 UTR (1188A/C) that was always encode products that regulate immune system associated with psoriasis. In this case, A was more activation. They are described below: common in cases.90 More recently, a global association PTPN22 (protein tyrosine phosphatase, non-receptor scan indicated that variants lying 60 kb upstream of the type 22) is expressed primarily in lymphoid tissues. The mRNA start site or in the 30 regulatory region of IL-12B R620W alteration of PTPN22 is associated with type-I are associated with psoriasis.91 Two missense changes diabetes, RA and SLE.81–83 When arginine is present, within a receptor subunit (IL-23R), were also reported to it is hypothesized that the protein can bind Csk and be associated with disease. This is interesting for a hence, prevent spontaneous T-cell activation by depho- number of reasons. IL-12 plays a key role in regulating sphorylation. When the autoimmune-associated trypto- both innate and adaptive immunity. It is a heterodimeric phan allele is present, PTPN22 can no longer bind molecule comprised of a subunit encoded by IL-12B Csk, and hence, a critical regulatory element of immune (p40) and a p35 subunit, which together form a p70 cell activation cannot be employed. Several studies molecule. This binds to a high affinity receptor, IL-12R. including our own have not revealed association of IL-12 is produced early on during infections or the psoriasis with PTPN22 SNPs. However, in one study inflammatory response by DCs and activated macro- from Germany, although association with 620W and phages.92 It acts together with IL-2 and TNF-a to induce psoriasis was not detected, significant association IFN-g expression in NK cells and acts on both CD8 þ T with one haplotype of the LD block encompassing cells and NK cells to enhance their toxicity. IL-12 also PTPN22 as well with another haplotype within an suppresses ultraviolet-mediated apoptosis of keratino- adjacent telomeric LD block was detected.84 This cytes by inducing DNA repair.93 IL-23 is an IL-12 suggests that other variants of PTPN22 may be asso- cytokine family member that shares the p40 subunit ciated with psoriasis. with IL-12. IL-23 has been proposed to be the main SUMO4: An M55V change within SUMO4, that cytokine stimulating a new lineage of effector CD4 þ T 94 encodes a small ubiquitin-like modifier 4 protein has cells called Th17 cells. These are distinct develop- 85 been shown to be associated with type-I diabetes. mentally and functionally from classical Th1 and Th2 SUMO4 binds I kappaB a and negatively regulates lineages and are characterized by production of IL-17. nuclear factor kappaB (NF-kB) transcriptional activity. Like Th1 and Th2, Th17 cells are proposed to have The M55 V substitution resulted in 5.5 times greater NF- evolved to provide adaptive immunity tailored to kB transcriptional activity and approximately 2 times specific classes of pathogens, such as extracellular greater expression of IL-12B, an NF-kB-dependent gene. bacteria. Aberrant Th17 responses have also been We examined association of this alteration with psoriasis implicated in a growing list of autoimmune disorders.95 using family-based methods and obtained a P-value of A change in IL-23R that led to less receptor function, 0.05, suggestive of association (Helms and Bowcock, would be expected to skew T-cell development in the unpublished results). The Rel/NF-kB transcription fac- direction of the Th1 class of T cells, which is clearly tors play a central role in numerous cellular processes, activated in psoriasis lesions.

Genes and Immunity Psoriasis: genetic associations YLiuet al 9 Interleukin cluster on chromosome 1q31–q32: This harbors 8 Ghadially R, Reed JT, Elias PM. Stratum corneum structure a 200 kb region containing genes for IL-10, MDA7, IL-19 and function correlates with phenotype in psoriasis. J Invest and IL-20. Association with genes in this region has Dermatol 1996; 107: 558–564. been investigated. Some evidence for association with 9 Allen M, Ishida-Yamamoto A, McGrath J, Davison S, Iizuka H, psoriasis and a haplotype harboring IL-19 and IL-20 Simon M et al. Corneodesmosin expression in psoriasis genes has been provided,96 albeit with modest P-values. vulgaris differs from normal skin and other inflammatory A polymorphic microsatellite in the IL-10 promoter skin disorders. Lab Invest 2001; 81: 969–976. 10 Abrams JR, Kelley SL, Hayes E, Kikuchi T, Brown MJ, Kang S also revealed evidence for association with psoriasis et al. 97 Blockade of T lymphocyte costimulation with cytotoxic T in patients with a family history of disease. Protective lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) effects conferred by some alleles and haplotypes reverses the cellular pathology of psoriatic plaques, including within this cluster of genes has also been proposed, the activation of keratinocytes, dendritic cells, and endothelial along with suggestions that some alleles influence cells. J Exp Med 2000; 192: 681–694. severity or clinical course of disease.98,99 A comprehen- 11 Ansel JC, Tiesman JP, Olerud JE, Krueger JG, Krane JF, Tara sive association analysis of alleles and haplotypes within DC et al. Human keratinocytes are a major source of cutaneous this cluster of genes is warranted in other patient platelet-derived growth factor. J Clin Invest 1993; 92: 671–678. populations. 12 Brown LF, Yeo KT, Berse B, Yeo TK, Senger DR, Dvorak HF et al. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med 1992; 176: 1375–1379. Conclusion 13 Viac J, Palacio S, Schmitt D, Claudy A. Expression of vascular endothelial growth factor in normal epidermis, epithelial Existing evidence supports the concept of psoriasis as a tumors and cultured keratinocytes. Arch Dermatol Res 1997; chronic inflammatory skin disorder, mediated by T cells, 289: 158–163. DCs and inflammatory cytokines. The availability of 14 Eckert RL, Broome AM, Ruse M, Robinson N, Ryan D, Lee K. methods to analyze tissue and large-scale genomic data S100 proteins in the epidermis. J Invest Dermatol 2004; 123: allow the identification of many cellular and gene 23–33. expression alterations in psoriatic lesions. A number of 15 Banno T, Adachi M, Mukkamala L, Blumenberg M. Unique chromosome regions that could harbor potential suscept- keratinocyte-specific effects of interferon-gamma that protect ibility loci to psoriasis are also being identified via large- skin from viruses, identified using transcriptional profiling. scale linkage and association studies. However, as with Antivir Ther 2003; 8: 541–554. 16 Banno T, Gazel A, Blumenberg M. Effects of tumor necrosis all complex disorders, these loci are not always been factor-alpha (TNF alpha) in epidermal keratinocytes revealed replicated in other pedigrees or cohorts, which can be using global transcriptional profiling. J Biol Chem 2004; 279: due to multiple confounding factors commonly seen in 32633–32642. genetic study of complex disorders. Moreover, the 17 Ferenczi K, Burack L, Pope M, Krueger JG, Austin LM. CD69, correlation between genetic predispositions and the HLA-DR and the IL-2R identify persistently activated T cells changes of cellular elements in psoriasis are still unclear in psoriasis vulgaris lesional skin: blood and skin comparisons at this point. Therefore, future research will focus on by flow cytometry. J Autoimmun 2000; 14: 63–78. integrating the knowledge of genetic variations into the 18 Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG. The picture of molecular and cellular mechanisms of psor- majority of epidermal T cells in psoriasis vulgaris lesions can iasis, which will in turn facilitates the discovery of novel produce type 1 cytokines, interferon-gamma, interleukin-2, therapeutic targets and the development of strategies for and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differ- individualized medicine. entiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 1999; 113: 752–759. 19 Vissers WH, Arndtz CH, Muys L, Van Erp PE, de Jong EM, References van de Kerkhof PC. Memory effector (CD45RO+) and cytotoxic (CD8+) T cells appear early in the margin zone of 1 Barisic-Drusko V, Rucevic I. Trigger factors in childhood spreading psoriatic lesions in contrast to cells expressing psoriasis and vitiligo. Coll Antropol 2004; 28: 277–285. natural killer receptors, which appear late. Br J Dermatol 2004; 2 Quesada JR, Gutterman JU. Psoriasis and alpha-interferon. 150: 852–859. Lancet 1986; 1: 1466–1468. 20 Bos JD, Hagenaars C, Das PK, Krieg SR, Voorn WJ, 3 Gilliet M, Conrad C, Geiges M, Cozzio A, Thurlimann W, Burg Kapsenberg ML. Predominance of ‘memory’ T cells (CD4+, G et al. Psoriasis triggered by toll-like receptor 7 agonist CDw29+) over ‘naive’ T cells (CD4+, CD45R+) in both normal imiquimod in the presence of dermal plasmacytoid dendritic and diseased human skin. Arch Dermatol Res 1989; 281: 24–30. cell precursors. Arch Dermatol 2004; 140: 1490–1495. 21 Rottman JB, Smith TL, Ganley KG, Kikuchi T, Krueger JG. 4 Zhou X, Krueger JG, Kao MC, Lee E, Du F, Menter A et al. Potential role of the chemokine receptors CXCR3, CCR4, and Novel mechanisms of T-cell and dendritic cell activation the integrin alphaEbeta7 in the pathogenesis of psoriasis revealed by profiling of psoriasis on the 63,100-element vulgaris. Lab Invest 2001; 81: 335–347. oligonucleotide array. Physiol Genomics 2003; 13: 69–78. 22 Austin LM, Coven TR, Bhardwaj N, Steinman R, Krueger JG. 5 Mansbridge JN, Knapp AM. Changes in keratinocyte Intraepidermal lymphocytes in psoriatic lesions are activated maturation during wound healing. J Invest Dermatol 1987; 89: GMP-17(TIA-1)+CD8+CD3+ CTLs as determined by pheno- 253–263. typic analysis. J Cutan Pathol 1998; 25: 79–88. 6 Hertle MD, Kubler MD, Leigh IM, Watt FM. Aberrant integrin 23 Yawalkar N, Schmid S, Braathen LR, Pichler WJ. Perforin and expression during epidermal wound healing and in psoriatic granzyme B may contribute to skin inflammation in atopic epidermis. J Clin Invest 1992; 89: 1892–1901. dermatitis and psoriasis. Br J Dermatol 2001; 144: 1133–1139. 7 Krane JF, Gottlieb AB, Carter DM, Krueger JG. The insulin-like 24 Chamian F, Lowes MA, Lin SL, Lee E, Kikuchi T, Gilleaudeau growth factor I receptor is overexpressed in psoriatic P et al. Alefacept reduces infiltrating T cells, activated epidermis, but is differentially regulated from the epidermal dendritic cells, and inflammatory genes in psoriasis vulgaris. growth factor receptor. J Exp Med 1992; 175: 1081–1090. Proc Natl Acad Sci USA 2005; 102: 2075–2080.

Genes and Immunity Psoriasis: genetic associations YLiuet al 10 25 Lowes MA, Chamian F, Abello MV, Fuentes-Duculan J, Lin SL, 45 Tazi Ahnini R, Camp NJ, Cork MJ, Mee JB, Keohane SG, Duff Nussbaum R et al. Increase in TNF-alpha and inducible nitric GW et al. Novel genetic association between the corneodes- oxide synthase-expressing dendritic cells in psoriasis and mosin (MHC S) gene and susceptibility to psoriasis. Hum Mol reduction with efalizumab (anti-CD11a). Proc Natl Acad Sci Genet 1999; 8: 1135–1140. USA 2005; 102: 19057–19062. 46 Simon M, Jonca N, Guerrin M, Haftek M, Bernard D, Caubet C 26 Wang F, Lee E, Lowes MA, Haider AS, Fuentes-Duculan J, et al. Refined characterization of corneodesmosin pro- Abello MV et al. Prominent production of IL-20 by CD68+/ teolysis during terminal differentiation of human epidermis CD11c+ myeloid-derived cells in psoriasis: gene regulation and its relationship to desquamation. J Biol Chem 2001; 276: and cellular effects. J Invest Dermatol 2006; 126: 1590–1599. 20292–20299. 27 Nestle FO, Turka LA, Nickoloff BJ. Characterization of dermal 47 Jonca N, Guerrin M, Hadjiolova K, Caubet C, Gallinaro H, dendritic cells in psoriasis. Autostimulation of T lymphocytes Simon M et al. Corneodesmosin, a component of epidermal and induction of Th1 type cytokines. J Clin Invest 1994; 94: corneocyte desmosomes, displays homophilic adhesive prop- 202–209. erties. J Biol Chem 2002; 277: 5024–5029. 28 Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, 48 Gallinaro H, Jonca N, Langbein L, Vincent C, Simon M, Serre Chamian F et al. Increased expression of interleukin 23 p19 G et al. A 4.2 kb upstream region of the human corneodesmo- and p40 in lesional skin of patients with psoriasis vulgaris. sin gene directs site-specific expression in hair follicles and J Exp Med 2004; 199: 125–130. hyperkeratotic epidermis of transgenic mice. J Invest Dermatol 29 Wollenberg A, Wagner M, Gunther S, Towarowski A, Tuma E, 2004; 122: 730–738. Moderer M et al. Plasmacytoid dendritic cells: a new 49 Veal CD, Capon F, Allen MH, Heath EK, Evans JC, Jones A cutaneous dendritic cell subset with distinct role in inflam- et al. Family-based analysis using a dense single-nucleotide matory skin diseases. J Invest Dermatol 2002; 119: 1096–1102. polymorphism-based map defines genetic variation at 30 Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. PSORS1, the major psoriasis-susceptibility locus. Am J Hum Interleukin-23 promotes a distinct CD4T cell activation state Genet 2002; 71: 554–564. characterized by the production of interleukin-17. J Biol Chem 50 Helms C, Saccone NL, Cao L, Daw JA, Cao K, Hsu TM et al. 2003; 278: 1910–1914. Localization of PSORS1 to a haplotype block harboring HLA- 31 Teunissen MB, Koomen CW, de Waal Malefyt R, Wierenga EA, C and distinct from corneodesmosin and HCR. Hum Genet Bos JD. Interleukin-17 and interferon-gamma synergize in the 2005; 118: 466–476. enhancement of proinflammatory cytokine production by 51 Nair RP, Stuart PE, Nistor I, Hiremagalore R, Chia NV, Jenisch human keratinocytes. J Invest Dermatol 1998; 111: 645–649. S et al. Sequence and haplotype analysis supports HLA-C as 32 Bowcock AM, Krueger JG. Getting under the skin: the the psoriasis susceptibility 1 gene. Am J Hum Genet 2006; 78: immunogenetics of psoriasis. Nat Rev Immunol 2005; 5:699–711. 827–851. 33 Lew W, Bowcock AM, Krueger JG. Psoriasis vulgaris: 52 Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, cutaneous lymphoid tissue supports T-cell activation and Donnelly P. A haplotype map of the human genome. Nature ‘Type 1’ inflammatory gene expression. Trends Immunol 2004; 2005; 437: 1299–1320. 25: 295–305. 53 Asumalahti K, Laitinen T, Lahermo P, Suomela S, Itkonen- 34 Lowes MA, Lew W, Krueger JG. Current concepts in the Vatjus R, Jansen C et al. Psoriasis susceptibility locus on 18p immunopathogenesis of psoriasis. Dermatol Clin 2004; 22: revealed by genome scan in Finnish families not associated 349–369, vii. with PSORS1. J Invest Dermatol 2003; 121: 735–740. 35 Kauffman CL, Aria N, Toichi E, McCormick TS, Cooper KD, 54 Tomfohrde J, Silverman A, Barnes R, Fernandez-Vina MA, Gottlieb AB et al. A phase I study evaluating the safety, Young M, Lory D et al. Gene for familial psoriasis suscept- pharmacokinetics, and clinical response of a human IL-12 p40 ibility mapped to the distal end of human chromosome 17q. antibody in subjects with plaque psoriasis. J Invest Dermatol Science 1994; 264: 1141–1145. 2004; 123: 1037–1044. 55 Tzschach A, Hoffmann K, Hoeltzenbein M, Bache I, Tommer- 36 Boehncke WH, Prinz J, Gottlieb AB. Biologic therapies up N, Bommer C et al. Molecular characterization of a for psoriasis. A systematic review. J Rheumatol 2006; 33: balanced chromosome translocation in psoriasis vulgaris. 1447–1451. Clin Genet 2006; 69: 189–193. 37 Ragaz A, Ackerman AB. Evolution, maturation, and regres- 56 Hwu WL, Yang CF, Fann CS, Chen CL, Tsai TF, Chien YH et al. sion of lesions of psoriasis. New observations and correlation Mapping of psoriasis to 17q terminus. J Med Genet 2005; 42: of clinical and histologic findings. Am J Dermatopathol 1979; 1: 152–158. 199–214. 57 Birnbaum RY, Zvulunov A, Hallel-Halevy D, Cagnano E, 38 Kurth I, Willimann K, Schaerli P, Hunziker T, Clark-Lewis I, Finer G, Ofir R et al. Seborrhea-like dermatitis with psoriasi- Moser B. Monocyte selectivity and tissue localization suggests form elements caused by a mutation in ZNF750, encoding a a role for breast and kidney-expressed chemokine (BRAK) in putative C2H2 zinc finger protein. Nat Genet 2006; 38: macrophage development. J Exp Med 2001; 194: 855–861. 749–751. 39 Elder JT, Nair RP, Guo SW, Henseler T, Christophers E, 58 Helms C, Cao L, Krueger JG, Wijsman EM, Chamian F, Voorhees JJ. The genetics of psoriasis. Arch Dermatol 1994; 130: Gordon D et al. A putative RUNX1 binding site variant 216–224. between SLC9A3R1 and NAT9 is associated with suscept- 40 Bowcock AM. Psoriasis genetics: the way forward. J Invest ibility to psoriasis (see comment). Nat Genet 2003; 35: Dermatol 2004; 122: xv–xvii. 349–356. 41 Tiilikainen A, Lassus A, Karvonen J, Vartiainen P, Julin M. 59 Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg Psoriasis and HLA-Cw6. Br J Dermatol 1980; 102: 179–184. L, Magnusson V et al. A regulatory polymorphism in PDCD1 42 Asumalahti K, Veal C, Laitinen T, Suomela S, Allen M, Elomaa is associated with susceptibility to systemic lupus erythema- O et al. Coding haplotype analysis supports HCR as the tosus in humans. Nat Genet 2002; 32: 666–669. putative susceptibility gene for psoriasis at the MHC PSORS1 60 Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, Sawada T locus. Hum Mol Genet 2002; 11: 589–597. et al. An intronic SNP in a RUNX1 binding site of 43 Allen MH, Veal C, Faassen A, Powis SH, Vaughan RW, SLC22A4, encoding an organic cation transporter, is asso- Trembath RC et al. A non-HLA gene within the MHC in ciated with rheumatoid arthritis (see comment). Nat Genet psoriasis. Lancet 1999; 353: 1589–1590. 2003; 35: 341–348. 44 Guerrin M, Vincent C, Simon M, Tazi Ahnini R, Fort M, Serre 61 Coffman JA. Runx transcription factors and the develop G. Identification of six novel polymorphisms in the human mental balance between cell proliferation and differentiation. corneodesmosin gene. Tissue Antigens 2001; 57: 32–38. Cell Biol Int 2003; 27: 315–324.

Genes and Immunity Psoriasis: genetic associations YLiuet al 11 62 Osato M, Yanagida M, Shigesada K, Ito Y. Point mutations of patibility complex susceptibility candidate loci in human the RUNx1/AML1 gene in sporadic and familial myeloid autoimmune diseases. Proc Natl Acad Sci USA 1998; 95: leukemias. Int J Hematol 2001; 74: 245–251. 9979–9984. 63 Fainaru O, Woolf E, Lotem J, Yarmus M, Brenner O, 81 Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Goldenberg D et al. Runx3 regulates mouse TGF-beta- Chokkalingam AP, Alexander HC et al. A missense single- mediated dendritic cell function and its absence results in nucleotide polymorphism in a gene encoding a protein airway inflammation. EMBO J 2004; 23: 969–979. tyrosine phosphatase (PTPN22) is associated with rheumatoid 64 Brenner O, Levanon D, Negreanu V, Golubkov O, Fainaru O, arthritis. Am J Hum Genet 2004; 75: 330–337. Woolf E et al. Loss of Runx3 function in leukocytes is 82 Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, associated with spontaneously developed colitis and Rostamkhani M et al. A functional variant of lymphoid gastric mucosal hyperplasia. Proc Natl Acad Sci USA 2004; tyrosine phosphatase is associated with type I diabetes. Nat 101: 16016–16021. Genet 2004; 36: 337–338. 65 Grueter B, Petter M, Egawa T, Laule-Kilian K, Aldrian CJ, 83 Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Wuerch A et al. Runx3 regulates integrin alpha E/CD103 and Carlton VE et al. Genetic association of the R620W poly- CD4 expression during development of CD4À/CD8+ T cells. morphism of protein tyrosine phosphatase PTPN22 with J Immunol 2005; 175: 1694–1705. human SLE. Am J Hum Genet 2004; 75: 504–507. 66 Capon F, Helms C, Veal CD, Tillman D, Burden AD, Barker JN 84 Huffmeier U, Steffens M, Burkhardt H, Lascorz J, Schurmeier- et al. Genetic analysis of PSORS2 markers in a UK dataset Horst F, Stander M et al. Evidence for susceptibility determi- supports the association between RAPTOR SNPs and familial nant(s) to psoriasis vulgaris in or near PTPN22 in German psoriasis. J Med Genet 2004; 41: 459–460. patients. J Med Genet 2006; 43: 517–522. 67 Hewett D, Samuelsson L, Polding J, Enlund F, Smart D, 85 Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D et al. A Cantone K et al. Identification of a psoriasis susceptibility functional variant of SUMO4, a new I kappa B alpha modifier, candidate gene by linkage disequilibrium mapping with a is associated with type 1 diabetes. Nat Genet 2004; 36: 837–841. localized single nucleotide polymorphism map. Genomics 86 Lizzul PF, Aphale A, Malaviya R, Sun Y, Masud S, 2002; 79: 305–314. Dombrovskiy V et al. Differential expression of phosphory- 68 Hebert SC, Mount DB, Gamba G. Molecular physiology of lated NF-kappaB/RelA in normal and psoriatic epidermis and cation-coupled Cl-cotransport: the SLC12 family. Pflugers Arch downregulation of NF-kappaB in response to treatment with 2004; 447: 580–593. etanercept. J Invest Dermatol 2005; 124: 1275–1283. 69 Huffmeier U, Lascorz J, Traupe H, Bohm B, Schurmeier-Horst 87 Mossner R, Kingo K, Kleensang A, Kruger U, Konig IR, Silm H F, Stander M et al. Systematic linkage disequilibrium analysis et al. Association of TNF-238 and -308 promoter polymorph- of SLC12A8 at PSORS5 confirms a role in susceptibility to isms with psoriasis vulgaris and psoriatic arthritis but not psoriasis vulgaris. J Invest Dermatol 2005; 125: 906–912. with pustulosis palmoplantaris. J Invest Dermatol 2005; 124: 70 Capon F, Novelli G, Semprini S, Clementi M, Nudo M, 282–284. Vultaggio P et al. Searching for psoriasis susceptibility genes in 88 Reich K, Westphal G, Schulz T, Muller M, Zipprich S, Fuchs T Italy: genome scan and evidence for a new locus on et al. Combined analysis of polymorphisms of the tumor chromosome 1. J Invest Dermatol 1999; 112: 32–35. necrosis factor-alpha and interleukin-10 promoter regions and 71 Bhalerao J, Bowcock AM. The genetics of psoriasis: a complex polymorphic xenobiotic metabolizing enzymes in psoriasis. disorder of the skin and immune system. Hum Mol Genet 1998; J Invest Dermatol 1999; 113: 214–220. 7: 1537–1545. 89 Litjens NH, van der Plas MJ, Ravensbergen B, Numan-Ruberg 72 Capon F, Semprini S, Dallapiccola B, Novelli G. Evidence for SC, van Assen Y, Thio HB et al. Psoriasis is not associated with interaction between psoriasis-susceptibility loci on chromo- IL-12p70/IL-12p40 production and IL12B promoter poly- somes 6p21 and 1q21. Am J Hum Genet 1999; 65: 1798–1800. morphism. J Invest Dermatol 2004; 122: 923–926. 73 Cookson WO, Ubhi B, Lawrence R, Abecasis GR, Walley AJ, 90 Tsunemi Y, Saeki H, Nakamura K, Sekiya T, Hirai K, Fujita H Cox HE et al. Genetic linkage of childhood atopic dermatitis to et al. Interleukin-12 p40 gene (IL12B) 30-untranslated region psoriasis susceptibility loci. Nat Genet 2001; 27: 372–373. polymorphism is associated with susceptibility to atopic 74 Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, dermatitis and psoriasis vulgaris. J Dermatol Sci 2002; 30: Liao H, Lee SP et al. Common loss-of-function variants of 161–166. the epidermal barrier protein filaggrin are a major predispos- 91 Begovich AB, Schrodi SJ, Leppert M, Krueger G, Cargill M. A ing factor for atopic dermatitis. Nat Genet 2006; 38: 441–446. genome-wide association study of putative functional SNPs 75 Morar N, Bowcock AM, Harper JI, Cookson WO, Moffatt MF. leads to the identification of two psoriasis loci – IL12B and Investigation of the chromosome 17q25 PSORS2 locus in IL23R – in 3 independent white North American sample sets. atopic dermatitis. J Invest Dermatol 2006; 126: 603–606. Am J Hum Genet 2006; Society meeting abstracts: A163. 76 Sagoo GS, Tazi-Ahnini R, Barker JW, Elder JT, Nair RP, 92 Trinchieri G. Cytokines and cytokine receptors. Immunol Rev Samuelsson L et al. Meta-analysis of genome-wide studies of 2004; 202: 5–7. psoriasis susceptibility reveals linkage to chromosomes 6p21 93 Beissert S, Ruhlemann D, Mohammad T, Grabbe S, El-Ghorr and 4q28–q31 in Caucasian and Chinese Hans population. A, Norval M et al. IL-12 prevents the inhibitory effects of cis- J Invest Dermatol 2004; 122: 1401–1405. urocanic acid on tumor antigen presentation by Langerhans 77 Foerster J, Nolte I, Schweiger S, Ehlert C, Bruinenberg M, cells: implications for photocarcinogenesis. J Immunol 2001; Spaar K et al. Evaluation of the IRF-2 gene as a candidate for 167: 6232–6238. PSORS3. J Invest Dermatol 2004; 122: 61–64. 94 Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy 78 Yan KL, Zhang XJ, Wang ZM, Yang S, Zhang GL, Wang J et al. TL, Murphy KM et al. Interleukin 17-producing CD4+ effector A novel MGST2 non-synonymous mutation in a Chinese T cells develop via a lineage distinct from the T helper type 1 pedigree with psoriasis vulgaris. J Invest Dermatol 2006; 126: and 2 lineages. Nat Immunol 2005; 6: 1123–1132. 1003–1005. 95 Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard 79 Yang S, Yan KL, Zhang XJ, Xiao FL, Fan X, Gao M et al. DC, Elson CO et al. Transforming growth factor-beta Systematic evaluation of association between the microsomal induces development of the T(H)17 lineage. Nature 2006; glutathione S-transferase 2 common variation and psoriasis 441: 231–234. vulgaris in Chinese population. Arch Dermatol Res 2006; 298: 96 Koks S, Kingo K, Vabrit K, Ratsep R, Karelson M, Silm H et al. 107–112. Possible relations between the polymorphisms of the cyto- 80 Becker KG, Simon RM, Bailey-Wilson JE, Freidlin B, Biddison kines IL-19, IL-20 and IL-24 and plaque-type psoriasis. Genes WE, McFarland HF et al. Clustering of non-major histocom- Immun 2005; 6: 407–415.

Genes and Immunity Psoriasis: genetic associations YLiuet al 12 97 Asadullah K, Eskdale J, Wiese A, Gallagher G, Friedrich M, polymorphism IL10.G and familial early onset psoriasis. Br J Sterry W. Interleukin-10 promoter polymorphism in psoriasis. Dermatol 2003; 149: 381–385. J Invest Dermatol 2001; 116: 975–978. 99 Kingo K, Koks S, Silm H, Vasar E. IL-10 promoter polymorph- 98 Hensen P, Asadullah K, Windemuth C, Ruschendorf F, isms influence disease severity and course in psoriasis. Genes Huffmeier U, Stander M et al. Interleukin-10 promoter Immun 2003; 4: 455–457.

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