DO: 0111286;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.33 | {Psoriasis susceptibility 1} | 177900 | Multifactorial | 3 | HLA-C | 142840 |
A number sign (#) is used with this entry because of evidence that susceptibility to psoriasis (PSORS1) is conferred by variation in MHC genes on chromosome 6p21 (see, e.g., HLA-C; 142840). The HLA-Cw6 allele (142840.0001) in particular is highly associated with the disease.
Psoriasis (psoriasis vulgaris; PV) is a chronic inflammatory dermatosis that affects approximately 2% of the population. It is characterized by red, scaly skin patches that are usually found on the scalp, elbows, and knees, and may be associated with severe arthritis. The lesions are caused by abnormal keratinocyte proliferation and infiltration of inflammatory cells into the dermis and epidermis. The usual age of onset of psoriasis is between 15 and 30 years, although it can present at any age (summary by Matthews et al., 1996).
Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein (123260) (summary by Marrakchi et al., 2011). GPP often presents in patients with existing or prior psoriasis vulgaris; however, GPP can develop without a history of PV (Sugiura et al., 2013). Palmoplantar pustulosis and acrodermatitis continua of Hallopeau represent acral forms of pustular psoriasis that have historically been grouped with GPP (summary by Setta-Kaffetzi et al., 2013).
Nestle et al. (2009) provided a detailed review of the pathogenesis and genetics of psoriasis.
Genetic Heterogeneity of Psoriasis and Psoriasis Susceptibility
PSORS2 (602723) is caused by mutation in the CARD14 gene (607211) on chromosome 17q25, and PSORS14 (614204) is caused by mutation in the IL36RN gene (605507) on chromosome 2q14.
Psoriasis susceptibility loci include PSORS1 on 6p21.3; PSORS3 (601454) on 4q; PSORS4 on 1q21; PSORS5 (604316) on 3q21; PSORS6 (605364) on 19p; PSORS7 (605606) on 1p; PSORS8 (610707) on 16q; PSORS9 (607857) on 4q31; PSORS10 (612410) on 18p11; PSORS11 (612599) on 5q31-q33; PSORS12 (612950) on 20q13; PSORS13 (614070), conferred by variation in the TRAF3IP2 gene (607043) on 6q21; and PSORS15 (616106), conferred by variation in the AP1S3 gene (615781) on 2q36.
An additional putative psoriasis candidate locus has been reported on 20p (Nair et al., 1997).
Selective skewing of autoreactive interferon-gamma (IFNG; 147570)-producing T helper cells (Th1) toward an interleukin-4 (IL4; 147780)-producing (Th2) phenotype can in experimental animals alleviate autoimmune disease without producing general immunosuppression. In a prospective dose escalation study, Ghoreschi et al. (2003) assessed treatment with human IL4 in 20 patients with severe psoriasis. The therapy was well tolerated, and within 6 weeks all patients showed decreased clinical scores and 15 improved more than 68%. Stable reduction of clinical scores was significantly better at 0.2 to 0.5 micrograms recombinant human IL4 than at less than 0.1 microgram (p = 0.009). In psoriatic lesions, treatment with 0.2-0.5 microgram/kilogram recombinant human IL4 reduced the concentrations of IL8 (146930) and IL19 (605687), 2 cytokines directly involved in psoriasis; the number of chemokine receptor CCR5+ (601373) Th1 cells; and the IFNG/IL4 ratio. In the circulation, 0.2-0.5 microgram/kilogram recombinant human IL4 increased the number of IL4+CD4+ T cells 2- to 3-fold. Thus, Ghoreschi et al. (2003) concluded that IL4 therapy can induce Th2 differentiation in human CD4+ T cells and has promise as a potential treatment for psoriasis.
Aberrant type 1 immune responses have been linked to the pathogenesis of psoriasis, and cytokines that elicit these immune responses may represent appropriate therapeutic targets, e.g., interleukin-12 (161560) and interleukin-23 (IL23A; 605580). Krueger et al. (2007) attested to the therapeutic effect of blocking these 2 interleukins by a fully human interleukin-12/23 monoclonal antibody. Antibody bound with high affinity to the common p40 subunit of human IL12 and IL23 (161561), neutralizing their bioactivity by blocking interactions with cognate cell-surface receptors. The authors found further evidence for therapeutic efficacy.
To provide clinical proof that specific targeting of IL23p19 results in symptomatic improvement of disease severity in human subjects, Kopp et al. (2015) evaluated tildrakizumab, a monoclonal antibody that targets the IL23p19 subunit, in a 3-part, randomized, placebo-controlled, sequential, rising multiple dose phase I study in patients with moderate to severe psoriasis. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg per kg groups by day 196. In part 2, 10 of 15 subjects in the 3 mg per kg group and 13 of 14 subjects in the 10 mg per kg group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate to severe psoriasis patients as demonstrated by improvements in PASI scores and histologic samples.
The multifactorial etiology of psoriasis is well established. Although environmental factors, such as streptococcal infections and stress affect the onset of the disease, family studies indicate a strong genetic component. Twin studies show the concordance in monozygotic twins to be 65 to 70% (Brandrup et al., 1982; Farber et al., 1974), compared to 15 to 20% in dizygotic twins. Family studies estimate the risk to first-degree relatives at between 8 to 23%.
A very large family tree was assembled in North Carolina by Abele et al. (1963). The authors concluded that penetrance was reduced to about 60%. The prevalence of arthritis was not increased in the psoriatic members of the kindred. Lomholt (1965) did a comprehensive study in the Faroe Islands. He found that 91% of patients had affected relatives. Transmission through many generations of many lines of the large kindred reported by Abele et al. (1963) supports dominant inheritance, the mode of inheritance espoused by Romanus (1945). Steinberg et al. (1951) suggested that homozygosity at 2 separate loci best explains their family data. Burch and Rowell (1965) suggested the existence of several distinct genotypes in psoriasis, i.e., genetic heterogeneity. Watson et al. (1972) concluded that the genetics is multifactorial.
Swanbeck et al. (1994) showed in a population genetic study that a recessive mode of inheritance was compatible with distribution among first-degree relatives, given a high gene frequency. Under these circumstances, a number of families will have a pseudodominant pattern of inheritance, i.e., one parent homozygous and the other heterozygous, giving a dominant-like pattern.
Happle (1991) invoked somatic recombination to explain linear psoriasis. He suggested that through somatic crossing-over in early development one of the daughter cells may become homozygous for a psoriasis gene and that this would be the stem cell of a clone proliferating in a linear pattern during development of the skin. For the ultimate manifestation of linear psoriasis, the presence of other predisposing genes as well as environmental factors would presumably be necessary. This would explain why linear psoriasis is usually absent at birth but develops later in life.
Rosbotham et al. (1994) described a British family in which psoriasis and multiple exostoses (133700) was associated in 4 members of 3 successive generations. A fifth member of the family, aged 27 years, in the third generation had only multiple exostoses. Rosbotham et al. (1994) raised the question of genetic linkage accounting for the cosegregation of the 2 disorders.
Swanbeck et al. (1997) presented empiric data useful in genetic counseling, based on information concerning first-degree relatives of 3,095 psoriatic probands. Altogether, 3,717 families with 1 or both parents who had psoriasis had been analyzed. The lifetime risk of getting psoriasis if no parent, 1 parent, or both parents have psoriasis was found to be 0.04, 0.28, and 0.65, respectively. If there was already 1 affected child in the family, the corresponding risks were 0.24, 0.51, and 0.83, respectively. The risk of getting psoriasis before the age of 32 years was dependent on the age of onset of psoriasis in 1 affected parent.
From studies in a 'skin equivalent model,' Saiag et al. (1985) concluded that the primary defect in psoriasis may reside in the dermal fibroblasts. Psoriatic fibroblasts could induce hyperproliferative activity in normal keratinocytes. The high rate of proliferation of psoriatic epidermis could not be suppressed by normal fibroblasts.
Psoriatic lesions are characterized by skin induration, scaling, and erythema accompanied by histologic evidence of inflammation, abnormal keratinocyte proliferation/terminal differentiation, and dermal angiogenesis. The inflammatory infiltrate, particularly pronounced at the dermal-epidermal junction, consists largely of activated T cells and antigen-presenting cells (APCs) and precedes the development of epidermal hyperproliferation. Increased levels of inflammatory cytokines are detectable in lesional psoriatic epidermis, which may result in the potentiation of T-cell activation (Chang et al., 1992) as well as hyperproliferation and accelerated differentiation of keratinocytes (Bata-Csorgo et al., 1995).
CTLA4Ig is a soluble chimeric protein consisting of the extracellular domain of the T-cell associated protein human CTLA4 (123890) and a fragment of the Fc portion of human IgG1 (147100). It binds to B7-1 (CD80; 112203) and to B7-2 (CD86; 601020) molecules on APCs and thereby blocks the CD28-mediated costimulatory signal for T-cell activation. Biologic activity of CTLA4Ig was demonstrated in a variety of animal models of transplantation (Sayegh and Turka, 1998) and autoimmunity (Reiser and Stadecker, 1996). In 43 patients with stable psoriasis vulgaris, Abrams et al. (1999) administered 4 infusions of CTLA4Ig. A 50% or greater sustained improvement in clinical disease activity was achieved in 46% of patients, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. There was no markedly increased rate of intralesional T-cell apoptosis, suggesting that the decreased number of lesional T cells was probably attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. The findings illustrated the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggested a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.
Lowes et al. (2005) reported that the number of CD11C (ITGAX; 151510)-positive cells expressing TNF (191160) and iNOS (NOS2A; 163730) exceeded the number of T cells in lesions of the dermis and epidermis of patients with psoriasis. These cells resembled murine Tnf- and iNos-producing dendritic cells, or 'Tip-DCs,' and did not express CD1A (188370) or the Langerhans cell marker langerin (604862). Treatment with efalizumab, an anti-CD11A (ITGAL; 153370) humanized monoclonal antibody, strongly reduced infiltration by these inflammatory DC-like cells prior to epidermal thinning and ameliorated disease manifestations.
Lande et al. (2007) identified the antimicrobial peptide LL37 (also known as CAMP, 600474) as the key factor that mediates plasmacytoid dendritic cell activation in psoriasis, a common autoimmune disease of the skin. LL37 converts inert self-DNA into a potent trigger of interferon production by binding the DNA to form aggregated and condensed structures that are delivered to and retained within early endocytic compartments in plasmacytoid dendritic cells to trigger Toll-like receptor-9 (605474). Lande et al. (2007) concluded that their data uncovered a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggested that this pathway may drive autoimmunity in psoriasis.
Conrad et al. (2007) showed that blocking the interaction of alpha-1 (192968)-beta-1 (135630) integrin (very late antigen-1, or VLA-1) with collagen prevented accumulation of epidermal T cells and immunopathology of psoriasis. Alpha-1-beta-1 integrin, a major collagen-binding surface receptor, was exclusively expressed by epidermal but not dermal T cells. Alpha-1-beta-1-positive T cells showed characteristic surface markers of effector memory cells and contained high levels of interferon-gamma (147570) but not interleukin-4 (147780). Blockade of alpha-1-beta-1 inhibited migration of T cells into the epidermis in a clinically relevant xenotransplantation model. This was paralleled by a complete inhibition of psoriasis development, comparable to that caused by tumor necrosis factor-alpha (TNFA; 191160) blockers. Conrad et al. (2007) concluded that their results defined a crucial role for alpha-1-beta-1 in controlling the accumulation of epidermal type 1 polarized effector memory T cells in a common human immunopathology and provided the basis for new strategies in psoriasis treatment focusing on T cell-extracellular matrix interactions.
Caruso et al. (2009) observed high IL21 (605384) protein and mRNA levels in skin lesions from patients with psoriasis compared to skin samples from nonlesional skin and from controls. IL21 was mostly produced by CD4+ T cells. IL21 transcript levels and IL21-expressing circulating T cells were also found in peripheral blood of individuals with psoriasis. Lesional skin, T cells, B cells, and natural killer cells expressed the IL21 receptor (IL21R; 605383). Treatment of keratinocytes from nonlesional skin caused epidermal hyperplasia and infiltration of the epidermis and dermis with inflammatory cells. In a human psoriasis xenograft mouse model, IL21 converted uninvolved skin into psoriatic plaques, and blockade of IL21 resolved inflammation and reduced keratinocyte proliferation. The findings indicated a role for IL21 in the epidermal hyperplasia of psoriasis.
By flow cytometric and immunohistochemical analyses, Tonel et al. (2010) demonstrated that expression of IL23 (see 605580) and IL23R (607562) was increased in the tissues of psoriasis patients. Injection of a neutralizing monoclonal antibody to IL23 in a xenotransplant mouse model showed IL23-dependent inhibition of psoriasis comparable to results obtained with anti-TNF blockers. Tonel et al. (2010) concluded that the IL23 pathway has a critical role in the pathogenesis of psoriasis.
Caution is necessary in the assessment of linkage to psoriasis susceptibility loci as a number of factors complicate the analyses (Matthews et al., 1996). These include incomplete penetrance, phenocopies, misdiagnosis, and the lack of a robust genetic model that accurately accounts for the observed familial aggregation.
Linkage to HLA
Russell et al. (1972) found that what was then termed HLA-A13, now HLA-B13 (see 142830) was present in 12 of 44 unrelated persons with psoriasis and in 3 of 89 controls (a difference significant at a probability less than 0.0001). W17 was present in 10 of 44 unrelated patients and in 17 family members with psoriasis in 4 generations. Two sibs did not have either psoriasis or W17. The study was undertaken because psoriasis is aggravated by streptococcal infection and a protein of group A beta-hemolytic streptococcus cross-reacts with certain HLA antigens. The finding of an HLA-B and disease association is an indication of polygenic inheritance. Even if there is a single major gene, the HLA-A locus must also be a factor. White et al. (1972) likewise found an excess of W17 and HLA-B 13 with a decrease in HLA-B12 in psoriatic patients. Psoriasis is rare in Eskimos, American Indians and Japanese, all of whom have a very low frequency of HLA-B13 and HLA-B17. Beckman et al. (1974) confirmed the high frequency of histocompatibility types W17 and HLA-B13. Familial psoriasis shows an association with HLA-BW17; psoriasis related to the streptococcus shows association with HLA-B13; and spondylitis occurring in psoriasis shows association with HLA-B2 (Arnett, 1977). HLA-Cw6 appears to be a psoriasis gene (Bodmer, 1978), judging by demonstration of close association. Using a sib-pair analysis, Suarez-Almazor and Russell (1990) found that all sib pairs shared at least one HLA haplotype and that 13 of the 15 were HLA identical, compared with an expected frequency of 4. From these results they concluded 'that at least one, and probably more, HLA-linked genes are implicated in the development of psoriasis.'
Tiilikainen et al. (1980) found a 20-fold increased risk of developing psoriasis in HLA-Cw6 carriers. The association between psoriasis and certain HLA alleles supports the hypothesis that psoriasis is a T cell-mediated autoimmune disorder.
In a study of 60 patients with early-onset psoriasis with a positive family history, 30 patients with late-onset psoriasis and no family history, and 146 ethnically matched blood donor controls, Schmitt-Egenolf et al. (1996) found that EH-57.1+ individuals had a 26-fold increased risk of developing early-onset psoriasis compared to individuals who were EH-57.1-negative. Within EH-57.1, HLA class I antigens were associated to a much greater extent with early-onset psoriasis than the HLA class II alleles.
Using data from 16 published datasets, Leder et al. (1998) found strong evidence for linkage between PSORS1 and HLA-B. The recombination fraction between PSORS1 and HLA-B was estimated to be at or near 0.00, with a maximum 2-point lod score of 23.7, assuming a dominant mode of inheritance with low (20%) penetrance at the PSORS1 locus. Although these families were geographically and ethnically diverse, there was no evidence for linkage heterogeneity. Although the HLA-B17 allele was strongly associated with psoriasis, Leder et al. (1998) concluded that it is unlikely per se to contribute directly to psoriasis susceptibility. They thought it more likely that the HLA-B locus is tightly linked to the PSORS1 locus. They raised the possibility of a 2-locus/heterogeneity model as a possible explanation for the various findings in the literature.
Jenisch et al. (1998) sought to provide more definitive evidence for linkage of psoriasis to HLA markers in multiplex families, to compare the major HLA risk alleles in these families with those determined by previous case-control studies, and to localize the gene more precisely. By applying the transmission/disequilibrium test (TDT) and parametric linkage analysis, they found evidence for linkage of psoriasis to the HLA cluster, particularly HLA-C. The data indicated that familial and 'sporadic' psoriasis share the same risk alleles. Leder and Hodge (1999) took Jenisch et al. (1998) to task for suggesting that the linkage of psoriasis susceptibility to HLA was not overpoweringly demonstrated by previous studies. They also urged that Jenisch et al. (1998) use the standard nomenclature for the psoriasis susceptibility locus on chromosome 6, PSORS1.
Association studies of Tazi Ahnini et al. (1999) suggested that polymorphism of the corneodesmosin gene (CDSN; 602593), located approximately 160 kb telomeric of the HLA-C locus, may be involved in susceptibility to psoriasis and may be the gene in the major histocompatibility complex (MHC) region responsible for the association with MHC.
Since psoriasis is considered a polygenic disorder, Capon et al. (1999) investigated the relationship between the HLA-C and 1q21 loci with respect to their contribution to psoriasis susceptibility. They first demonstrated an association with Cw6 in a sample of 1q-linked pedigrees by means of the transmission/disequilibrium test. In the second phase of the study, Capon et al. (1999) subjected fifteen 1q-linked families to an analysis of the correlation between the nonparametric linkage scores at HLA-C and D1S305. Data could be interpreted as preliminary evidence of an epistatic interaction between the 1q21 and 6p21 psoriasis-susceptibility loci. In the third aspect of the study, they found a significant increment of the 'weighted' lod score with respect to the baseline lod. This provided the first significant evidence for linkage in the Italian population with the HLA region. Only the assumption of interaction allowed the authors to replicate the linkage to the HLA region. This suggested that some of the difficulties in replication of results obtained in genome scans for psoriasis susceptibility and, more generally, for complex disorders may be smoothed in the future by analyses allowing identification of potential interactions.
Using a total of 14 highly polymorphic markers in the 6p21.3 region, Balendran et al. (1999) localized a major psoriasis susceptibility gene in a 285-kb genomic region near HLA-C.
By genotyping 76 unrelated Japanese psoriasis patients at 11 polymorphic markers, Oka et al. (1999) defined a 111-kb critical region located 89 to 200 kb telomeric to HLA-C.
Nair et al. (2000) localized the PSORS1 locus to a 60-kb interval telomeric to HLA-C. To narrow the interval for candidate gene testing, they performed a linkage-disequilibrium analysis of 339 families, with the use of 62 physically mapped microsatellite markers spanning the MHC. As detected by the use of a TDT, individual markers yielded significant linkage disequilibrium (LD) across most of the MHC. However, the strongest evidence for marker-trait disequilibrium was found in an approximately 300-kb region extending from the MICA gene (600169) to the CDSN gene.
Mallon et al. (2000) determined the HLA-Cw*0602 allele was present in 100% of 29 Caucasian patients with guttate psoriasis presenting consecutively with guttate psoriasis associated with a history of a sore throat and/or an antistreptolysin O titer greater than 200 IU mL(-1). This allele was present in only 20% of a control population of 604 random Caucasian cadaver donors. Mallon et al. (2000) concluded that HLA-Cw*0602 is likely to play a direct part in the pathogenesis of guttate psoriasis.
Gonzalez et al. (2000) examined a Spanish sample of 95 patients with early-onset chronic plaque psoriasis and 104 Spanish matched controls to investigate whether HLA-Cw*0602 or other closely related class I loci might play a part in disease development. They demonstrated a significant increase of Cw*0602 in psoriasis patients (odds ratio = 3.64; p(c) less than 0.0006). They also found a significant association between the beta allele of octamer transcription factor-3 (OCT3; 164177) (HindIII) and psoriasis (odds ratio = 3.76; p(c) less than 0.0003). The OCT3-beta allele (etiologic fraction = 0.62) was more strongly associated with psoriasis vulgaris than Cw*0602 (etiologic fraction = 0.35), and the increase of OCT3-beta allele was independent of the linkage disequilibrium with Cw*0602, as this was also found in Cw*0602-negative patients (odds ratio = 3.63; p(c) less than 0.015, etiologic fraction = 0.55). The data of Gonzalez et al. (2000) suggested that the psoriasis susceptibility gene is located within a critical region of 147 kb, telomeric to HLA-C and centromeric to the corneodesmosin gene, and the association of Cw6 to psoriasis may be secondary to linkage disequilibrium.
In 52 Caucasian nuclear families with chronic stable early-onset psoriasis, each with 1 affected child, Schmitt-Egenolf et al. (2001) tested for locus interaction using the HLA haplotype EH-57.1/I and the CDSN haplotype formed by 3 intragenic variant sites at nucleotides 619 (T), 1236 (T), and 1243 (C). On direct comparison of their contributions, the corneodesmosin TTC haplotype was more closely associated with psoriasis than EH-57.1/I by 1 order of magnitude, and there was no higher order interaction between psoriasis, HLA, and CDSN. Schmitt-Egenolf et al. (2001) suggested that there are 2 independent genetic contributions to psoriasis within the MHC.
Veal et al. (2001) performed a genomewide linkage analysis using 271 polymorphic markers in 284 sib pairs from 158 independent families. They identified linkage at 6p21 (PSORS1) with a nonparametric linkage score (NPL) of 4.7 and at a novel locus on 1p (PSORS7; 605606) with an NPL of 3.6 in all families studied.
Studies refining the localization of the PSORS1 gene have highlighted linkage disequilibrium (LD) with psoriasis along a 150-kb segment that includes at least 3 candidate genes, each of which had been shown to harbor disease-associated alleles: HLA-C (142840), alpha-helix coiled-coil rod homolog (HCR; 605310), and CDSN (602593). To establish a high-resolution genetic characterization of the PSORS1 locus, Veal et al. (2002) resequenced genomic segments along a 220-kb region of chromosome 6p21 and identified 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding) whose position was representative of the overall marker distribution, they genotyped a dataset of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted 2 SNPs, which Veal et al. (2002) designated n.7 and n.9, lying 7 and 4 kb proximal to HLA-C, respectively. These markers generated highly significant evidence of disease association, several orders of magnitude greater than the observed significance displayed by any other SNP that had previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control dataset. The only markers exclusive to the overtransmitted chromosomes were the SNPs n.7 and n.9, which defined a 10-kb PSORS1 core risk haplotype.
To investigate the psoriasis susceptibility loci in Chinese Hans, Zhang et al. (2002) performed a genomewide scan with 2-point and multipoint parametric and nonparametric linkage analyses in 61 multiplex Han families residing in east and southeast China, comprising 189 affected and 166 unaffected individuals. Zhang et al. (2002) confirmed linkage at 6p21 (PSORS1) with nonparametric linkage scores greater than 3 in the range of 39.9-62.3 cM and a maximum multipoint nonparametric linkage score of 4.58 (p = 0.000032). Parametric analysis revealed a maximum 2-point heterogeneity lod score of 4.30 with 58% as the proportion of linked families (alpha) and a maximum multipoint heterogeneity lod score of 4.25 (alpha = 53%) under the assumption of a dominant model.
Orru et al. (2005) undertook fine mapping of the PSORS1 locus in the major histocompatibility complex at 6p21.3. They set up a study using 17 polymorphic markers in a 525-kb interval around the HLA-C locus. The results uncovered 5 loci with alleles strongly associated with psoriasis, all structured in a psoriasis-susceptibility haplotype (PSH). Subsequent analysis of extended haplotypes showed that the PSH was not only present in the traditional psoriasis-susceptibility extended haplotypes but also on a haplotype of Sardinian origin found to be associated with psoriasis because of an ancestral recombination with one of the susceptibility haplotypes carrying a particular HLA-C allele. Comparisons of the regions identical by descent among associated and nonassociated haplotypes highlighted a minimum region of 70 kb not recombinant with PSORS1, surrounding the CDSN gene (602593).
Helms et al. (2005) performed a comprehensive case/control and family-based association study on 572 northern Europeans with psoriasis from 242 families and 332 controls. The strongest association was found with single markers and haplotypes from a linkage disequilibrium block harboring HLA-C and SNP n.9 (rs10456057). Logistic regression analyses indicated that association seen with candidate genes CDSN and HCR (605310) was entirely dependent on association with HLA-Cw*0602 and SNP n.9-G alleles, and the authors concluded that PSORS1 lies on the haplotype block containing HLA-C and SNP n.9. Helms et al. (2005) also identified a rare overtransmitted HLA-C allele, HLA Cw*1203, which shares identical sequences with HLA-Cw*0602 in its alpha-2 domains and 3-prime introns, including a putative binding site for the RUNX/AML (see 151385) family of transcription factors.
Interaction between PSORS1 and PSORS6 Loci
In a family with an early-onset form of psoriasis vulgaris, Huffmeier et al. (2009) performed a linkage disequilibrium study and found evidence for association with a newly discovered microsatellite at 19p13 (D19SPS21; p less than 5.3 x 10(-5)) within the region of the PSORS6 locus (605364). An LD-based association scan in 300 trios revealed association with several single SNPs in 1 LD block. When Huffmeier et al. (2009) stratified this cohort for carrying the PSORS1 risk allele at the HLA-C locus (Cw*0602), evidence for association became much stronger at single SNP and haplotype levels (p values between 1.0 x 10(-4) and 8.0 x 10(-4)). In a replication study of 1,114 patients and 937 control individuals, evidence for association was also observed after stratification to the PSORS1 risk allele. In both study groups, logistic regression showed evidence for interaction between the risk alleles at PSORS1 and PSORS6. Best p values for rs12459358 in both groups remained significant after correction for multiple testing. Huffmeier et al. (2009) concluded that their data identified a susceptibility factor at PSORS6 that is relevant in patients with early-onset psoriasis vulgaris carrying the PSORS1 risk allele.
Other Linkage
Trembath et al. (1997) used a 2-stage approach to search the human genome for genes conferring susceptibility to psoriasis, using a total of 106 affected sib pairs identified from 68 independent families. As over one-third of the extended kindreds included affected relatives besides sibs, in addition to an analysis of allele sharing between affected sibs, a novel linkage strategy was applied that extracted full nonparametric information. Four principal regions of possible linkage were identified on chromosomes 2, 8, and 20, and markers from the MHC region at 6p21 showed highly significant evidence of linkage disequilibrium. Data from limited case-control associations had previously implicated the MHC; this study demonstrated that a gene or genes located within the MHC and close to class I HLA loci represent the major determinant of the genetic basis of psoriasis.
In a 12.5-cM genomewide scan for psoriasis susceptibility loci by recombination-based tests, Nair et al. (1997) found linkage to the HLA region (maximum lod = 3.52), as well as suggestive linkage to 2 novel regions: 16q (see PSORS8, 610707) and 20p (maximum lod = 2.62). All 3 regions yielded p values equal to or less than 0.01 by nonparametric analysis. Recombination-based and allele sharing methods also confirmed a previous report of a dominant susceptibility locus on distal 17q. Nair et al. (1997) could not confirm a previously reported locus on distal 4q. Taken together with the demonstrated linkage to HLA-B (142830) and HLA-C (142840), this genomewide scan identified a psoriasis susceptibility locus at HLA, confirmed linkage to 17q (PSORS2; 602723), and recommended 2 novel genomic regions for further scrutiny. The PSORS8 region on 16q overlaps with a susceptibility locus for Crohn disease (IBD1; 266600). Nair et al. (1997) noted that psoriasis is more common in patients with Crohn disease than in controls, suggesting that an immunomodulatory locus capable of influencing both diseases may reside in this region.
Burden et al. (1998) performed linkage studies involving 395 individuals from 103 psoriasis families. In the population from which the probands were drawn, there was evidence of a parental sex effect, more probands having an affected father than an affected mother. Genetic anticipation was also apparent and most marked if the disease was inherited from the father. They could not replicate the alleged linkage with loci on chromosome 17 (PSORS2; 602723) and chromosome 4 (PSORS3; 601454). The evidence for linkage in sib-pair analysis was greatest when the allele was of paternal origin and was most significant in those families without psoriatic arthritis. The studies confirmed the presence of a susceptibility gene on 6p. The authors interpreted the evidence to suggest that a different genetic susceptibility may underlie psoriasis and psoriatic arthritis.
Chen et al. (1996) showed that the clinical response of psoriasis to 1,25-dihydroxyvitamin D3 is correlated with the vitamin D receptor (601769) mRNA expression level, which may be influenced by the genotype of the vitamin D receptor, which maps to 12q12-q14. Park et al. (1999) typed the vitamin D receptor gene in 104 psoriasis patients and 104 healthy controls, all of Korean descent, with respect to the ApaI RFLP alleles (A or a). A significant increase in the frequency of the A allele (absence of the restriction site at intron 8) was observed in psoriasis patients as compared with that of the control group. This tendency was more marked in early-onset psoriasis. These findings suggested that allelic variance in the vitamin D receptor gene itself or other genes in linkage disequilibrium with this gene could predispose to the development of psoriasis.
Enlund et al. (1999) performed complete multipoint parametric and nonparametric linkage analysis in 104 Swedish families (153 sib pairs) between the reported major psoriasis susceptibility loci on chromosome 4q, 6p and 17q and polymorphic microsatellite markers in their vicinity. They confirmed a significant linkage to HLA region on 6p but only a suggestive linkage to 17q and no linkage to 4q.
Asumalahti et al. (2000) determined the structure of a gene, HCR (605310), previously identified by Oka et al. (1999), from the PSORS1 region. An association study among 100 Finnish psoriasis families revealed that 2 single-nucleotide polymorphisms (SNPs) in exon 2 of HCR associated significantly with psoriasis and occurred together. Association analysis did not support CDSN allele 5 (CDSN*5; defined by 619T and 1243C) as a psoriasis susceptibility allele in their sample. HCR was overexpressed in keratinocytes of psoriatic lesions compared with paired samples of healthy skin. The authors suggested a potential role for HCR in the pathogenesis of psoriasis.
Asumalahti et al. (2002) genotyped 419 psoriasis families at selected HLA loci. A conserved allele of HCR, *WWCC, was highly associated with psoriasis and with the HLA-Cw6 allele. Because of strong linkage disequilibrium between HLA-Cw6 and HCR*WWCC, the 2 genes could not be genetically distinguished by this sample size. The variant HCR allele was predicted to differ in secondary structure from the wildtype protein by extending the length of the first alpha-helical loop. Furthermore, the pattern of HCR protein expression in lesional psoriatic skin differed from normal skin, as shown by immunocytochemistry. The authors hypothesized that the HCR*WWCC allele may be a major genetic determinant for psoriasis, possibly by impacting on keratinocyte proliferation.
O'Brien et al. (2001) investigated the HCR gene for disease association by direct sequencing of 9 PCR products amplified from a series of Swedish psoriasis patients and controls. They found that HCR is a highly polymorphic gene, with 25 polymorphisms in the open reading frame alone, of which 10 demonstrated disease association; however, the relationship between HCR polymorphisms and HLA-Cw*0602 indicated that HCR cannot truly be considered a likely candidate gene. They investigated the Cw*0602 association while stratifying for HCR single-nucleotide polymorphisms. They also investigated HCR single-nucleotide polymorphism association with the disease while stratifying for the presence of Cw*0602. O'Brien et al. (2001) found that for whichever single-nucleotide polymorphism that was stratified, there was still a strongly significant Cw*0602 association with psoriasis; however, when they stratified for Cw*0602 presence, only 1 silent polymorphism showed significant association. O'Brien et al. (2001) concluded that HCR polymorphisms display association with psoriasis due to linkage disequilibrium with Cw*0602 and are, therefore, unlikely to be directly involved in the development of psoriasis.
To confirm previously reported linkages to psoriasis, the International Psoriasis Genetics Consortium (2003) analyzed 942 ASPs from 710 pedigrees for 53 polymorphic microsatellites spanning 14 psoriasis candidate regions. Maximum lod score (MLS) analysis of ASPs yielded allele sharing of 60% for markers within the MHC. Across the remainder of the genome, the strongest evidence of allele sharing was obtained on 16q and 10q22-q23. In agreement with previous studies, strong linkage disequilibrium was also observed between psoriasis and the MHC. The authors identified 2 psoriasis-associated MHC haplotypes with the haplotype-based TDT. Analysis of only those families carrying either of these haplotypes significantly increased the 16q lod score from 1.3 to 2.4. These results underscored the importance of the MHC in psoriasis and provided a rationale for examination of candidate regions on chromosomes 16q and 10q in more detail.
In a metaanalysis involving multiple studies of patients with psoriasis, Li et al. (2009) found independent associations between disease and SNPs in 2 different genes: rs6908425 in the CDKAL1 gene (611259) on 6p22 (p = 1.57 x 10(-5) in 3,206 cases and 4,529 controls), and rs3789604 in the PTPN22 gene (600716) on 1p13 (p = 3.45 x 10(-5) in 2,823 cases and 4,066 controls). A smaller association was observed for rs597980 in the ADAM33 gene (607114) on 1p13 (p = 0.0057 in 2,025 cases and 1,597 controls).
HLA Association Studies
Gudjonsson et al. (2002) typed 369 patients with familial psoriasis for HLA-C and compared the clinical features of the patients carrying HLA-Cw6 with those carrying other HLA-C types. Patients who are Cw6-positive had a lower age at onset. Cw6-positive women had an earlier disease onset than Cw6-positive men, but such a difference was not observed for the Cw6-negative patients. The guttate-type onset of psoriasis was mostly confined to the Cw6-positive group, and persistent disseminated guttate-like papules were also predominantly observed in the Cw6-positive patients. The Cw6-positive patients also had more extensive plaques on their arms, legs, and trunk, more severe disease, higher incidence of the Koebner phenomenon, worsening of psoriasis during or after throat infections, and more often a favorable response to sunlight. In contrast, dystrophic nail changes were more common in the Cw6-negative patients. Gudjonsson et al. (2002) concluded that patients with psoriasis have different clinical features depending on whether they are HLA-Cw6-positive or -negative.
To ascertain whether there are differences in the clinical features and relative risk between HLA-Cw*0602 homozygous and heterozygous psoriasis patients, Gudjonsson et al. (2003) evaluated 1,006 patients with chronic plaque psoriasis. Patients and 512 unrelated controls were typed for HLA-C. Of the patients, 646 (64.2%) were HLA-Cw*0602-positive, and 68 (6.8%) were homozygous for this allele. Heterozygosity was associated with a relative risk of developing psoriasis of 8.9 compared with 23.1 for the Cw6 homozygous patients. The homozygous patients also had an earlier disease onset. However, the Cw6 homozygotes did not differ from the heterozygotes with respect to disease severity, guttate onset, distribution of plaques, nail changes, or any other clinical parameter recorded. Gudjonsson et al. (2003) concluded that homozygosity for HLA-Cw*0602 has a major additive impact on the risk of developing psoriasis and predisposes to an earlier disease onset, but does not have any marked influence on the phenotype or the severity of the disease.
Asumalahti et al. (2003) genotyped 3 psoriasis vulgaris susceptibility alleles of the PSORS1 locus (HLA-Cw*6, HCR*WWCC, and CDSN*5) in 2 clinical variants of psoriasis (guttate psoriasis and palmoplantar pustulosis; see 614204) to study whether PSORS1 is also involved in the pathogenesis of these variants. They asked whether these 2 clinical subgroups could help distinguish the causative gene within the high-risk PSORS1 haplotype. Asumalahti et al. (2003) found that association of guttate psoriasis with the 3 PSORS1 susceptibility alleles was similar and even stronger than seen with psoriasis vulgaris. Palmoplantar pustulosis, however, did not show association with any of the 3 candidate genes at this locus. No correlation with the age of onset for disease was observed. The results of Asumalahti et al. (2003) showed conclusively that psoriasis vulgaris and guttate psoriasis have a similar genetic basis for their association to PSORS1, whereas palmoplantar pustulosis appears to be a distinct disorder.
Nair et al. (2006) presented evidence that the HLA-C gene (142840) is the PSORS1 gene and that HLA-Cw6 (142840.0001) is the PSORS1 risk allele conferring susceptibility to early-onset psoriasis.
In a genomewide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls and a replication of 9,079 European samples, The Genetic Analysis of Psoriasis Consortium and The Wellcome Trust Case Control Consortium 2 (2010) reported compelling evidence for an interaction between the HLA-C locus and the ERAP1 (606832) locus on chromosome 5q15, with a combined P value of 6.95 x 10(-6). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants influenced psoriasis susceptibility only in individuals carrying the HLA-C risk allele rs10484554A, also known as CW*0602. When compared with the most protective 2-locus genotype, homozygosity for the A allele at the HLAC SNP rs10484554 and the A allele at ERAP1 SNP rs27524 conferred a more than 15-fold odds ratio of psoriasis with a 95% confidence interval of 7.5 to greater than 30.
In a metaanalysis of rare variants in the CARD14 gene (607211) in 7 psoriasis cohorts involving more than 6,000 cases and 4,000 controls, Jordan et al. (2012) found association between psoriasis (PSORS2; 602723) and the SNP rs11652075 (R820W; p = 2.1 x 10(-6)). Evidence for association increased in 2 cohorts of European ancestry when the PSORS1 variant HLA-Cw*0602 (SNP rs10484554) was included as a covariate, suggesting a genetic connection between PSORS1 and PSORS2.
Other Association Studies
The psoriatic inflammatory process is characterized by an overexpression of proinflammatory cytokines such as tumor necrosis factor-alpha (TNFA; 191160) and interleukin-1-beta (IL1B; 147720) compared with a relative deficiency of antiinflammatory factors such as IL10 (124092) and the interleukin-1 receptor antagonist (IL1RA; 147679). Gene polymorphisms that affect cytokine production may contribute to the disease-associated cytokine imbalance and influence susceptibility to psoriasis. Reich et al. (2002) investigated the relationship between polymorphisms in the genes encoding TNFA (G-238A; G-308A, 191160.0004), IL1B (C-511T, T+3953C), and IL1RA (intron 2), and cytokine production in peripheral blood mononuclear cells of healthy donors, and analyzed the distribution of these polymorphisms in 231 patients with psoriasis vulgaris and 345 healthy controls. Carriage of TNFA A-238 allele 2 (-238*A) was associated with increased production of TNFA in response to lipopolysaccharide in vitro, and with early-onset disease (younger than 40 years), especially in male patients with psoriasis. Carriage of the IL1B-511*1 (-511*C) homozygous genotype was associated with increased production of IL1RA in response to lipopolysaccharide and Il10, and with late-onset psoriasis. These findings indicated that gene polymorphisms associated with altered cytokine responses in vitro may modify age of onset of psoriasis.
IL10 is thought to play a key role in psoriasis. Its promoter is highly polymorphic, with 2 informative microsatellites, interleukin-10.G and interleukin-10.R. To understand whether IL10 is a predisposing gene for psoriasis susceptibility, Asadullah et al. (2001) analyzed IL10 promoter polymorphisms in 78 patients and 80 healthy controls. The distribution of IL10.G and IL10.R microsatellite alleles did not vary between patients and controls. In addition, when the psoriasis patients were stratified according to age of onset (younger than 40, or 40 and older), no difference in allele distribution was observed; however, a clear differential distribution was revealed at the IL10.G locus when patients were stratified according to whether they had a positive family history of psoriasis (p = 0.04). This difference was due to an overrepresentation of the IL10.G13 allele in those patients with familial disease (40.4% vs 19.6%, chi square = 7.292, p = 0.007). The positive association of allele IL10.G13 with familial psoriasis was especially strong when patients with early onset were compared with those with early onset against a nonfamilial background (39.6% vs 14.5%, chi square = 8.959, p = 0.003). Patients with age of onset of less than 40 were 4-fold more likely to have a psoriatic family background if they carried the IL10.G13 allele. These data suggested that the IL10 locus contributes to the heritability of psoriasis susceptibility.
Using multiplex amplifiable probe hybridization (MAPH) and paralog ratio test (PRT), Hollox et al. (2008) reported an association between increased copy number variation at the beta-defensin gene cluster (see DEFB4; 602215) on chromosome 8p23.1 and psoriasis among 179 Dutch patients and 272 controls (p = 7.8 x 10(-5)). A second cohort of 319 German patients and 305 controls assayed using PRT confirmed the finding (p = 2.95 x 10(-5)). Hollox et al. (2008) suggested that high levels of beta-defensins may result in an inappropriate inflammatory response after minor skin injury in patients with psoriasis.
Haskamp et al. (2020) studied 74 patients with generalized pustular psoriasis (GPP; see PSORS14, 614204), 2 with acute generalized exanthematous pustulosis, and 6 with an acral form of the disorder. They identified mutations in the MPO gene (606989) in 17 of the patients, 4 with biallelic variants and 13 with a single MPO variant. Some of these variants had previously been reported in asymptomatic individuals with MPOD (254600). Further analysis of exome data revealed that 5 of the 17 individuals with MPO mutations were heterozygous or homozygous for mutations in the IL36RN gene (605507). The authors suggested that GPP has an oligogenic inheritance pattern, and that MPO mutations explain part of the reduced penetrance and variable age of onset in GPP.
Vergnano et al. (2020) performed whole-exome sequencing in 19 unrelated patients with GPP and identified 4 patients with biallelic variants in the MPO gene, 1 of whom also carried a known pustular psoriasis-associated variant in the AP1S3 gene (615781; see PSORS15, 616106). Cell culture experiments revealed downregulation of neutrophil apoptosis in the absence of MPO activity. The authors stated that their findings and those of Haskamp et al. (2020) demonstrated a significant association between MPO mutations and pustular skin disease. Noting that they did not observe any evidence of immune deficiency in their study patients, and that pustular skin disease had been reported in only a fraction of people affected by MPOD, Vergnano et al. (2020) suggested that the manifestations of MPO mutations may be influenced by background polygenic variation.
Boyman et al. (2004) engrafted keratome biopsies of human symptomless prepsoriatic skin onto AGR129 mice, which are deficient in type I and type II interferon receptors (see 107450 and 107470, respectively), as well as Rag2 (179616), and thereby lack B and T cells and show severely impaired NK cell activity. Upon engraftment, human T cells underwent local proliferation, which was crucial for development of a psoriatic phenotype exhibiting papillomatosis and acanthosis. Immunohistochemical analysis of prepsoriatic skin before transplantation and 8 weeks after transplantation showed activation of epidermal keratinocytes, dendritic cells, endothelial cells, and immune cells in the transplanted tissue. T-cell proliferation and the subsequent disease development were dependent on TNF production and could be inhibited by antibody or soluble receptor to TNF. Boyman et al. (2004) concluded that TNF-dependent activation of resident T cells is necessary and sufficient for development of psoriatic lesions.
Elomaa et al. (2004) engineered transgenic mice with either a nonrisk allele of HCR (605310) or the HCR*WWCC risk allele under the control of the cytokeratin-14 (KRT14; 148066) promoter. Transgenic mice appeared phenotypically normal, and histologically their skin was indistinguishable from wildtype mice. Comparison of gene expression changes using microarrays between nonrisk and risk allele mice revealed similarities to previous observations in human psoriatic skin, including upregulation of cytokeratins 6 (KRT6A; 148041), 16 (KRT16; 148067), and 17 (KRT17; 148069) in risk allele mice. There were also changes in the expression of genes associated with terminal differentiation and formation of the cornified cell envelope. The authors concluded that HCR may constitute a susceptibility gene in the PSORS1 locus.
Zenz et al. (2005) reported that in psoriatic lesions, epidermal keratinocytes have decreased expression of JunB (165161), a gene localized in psoriasis susceptibility region PSORS6 (605364). They designed inducible, conditional, single- and double-knockout mice for JunB and c-Jun (165160). Mutant mice and littermate controls were treated with tamoxifen at 8 weeks of age. Single-mutant mice did not show any skin phenotype up to 2 months after deletion. However, in JunB/c-Jun double-mutant mice, alterations to the hairless skin appeared 8 to 10 days after tamoxifen induction. After 18 days of tamoxifen treatment, 100% of the double-mutant mice showed a strong phenotype with scaly plaques affecting primarily ears, paws, and tail, and less frequently the hairy back skin. Histology of affected skin from mutant mice showed the hallmarks of psoriasis, such as a strongly thickened epidermis with prominent rete ridges, thickened keratinized upper layers (hyperkeratosis) and parakeratosis (nucleated keratinocytes in the cornified layer) and increased subepidermal vascularization. Arthritic lesions strongly reminiscent of psoriatic arthritis were observed with 100% penetrance. In contrast to the skin phenotype, the development of arthritic lesions required T and B cells and signaling through tumor necrosis factor receptor-1 (TNFR1; 191190). Prior to the disease onset, 2 chemotactic proteins (S100A8, 123885 and S100A9, 123886), which map to the psoriasis susceptibility region PSORS4 (603935), were strongly induced in mutant keratinocytes in vivo and in vitro. Zenz et al. (2005) proposed that the abrogation of JunB/activator protein-1 (AP1) in keratinocytes triggers chemokine/cytokine expression, which recruits neutrophils and macrophages to the epidermis, thereby contributing to the phenotypic changes observed in psoriasis. Thus, their data support the hypothesis that epidermal alterations are sufficient to initiate both skin lesions and arthritis in psoriasis.
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