Psoriasis 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. ... Psoriasis 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). Nestle et al. (2009) provided a detailed review of the pathogenesis and genetics of psoriasis. - Genetic Heterogeneity of Psoriasis Susceptibility Several psoriasis susceptibility loci have been mapped: PSORS1 on 6p21.3; PSORS2 (602723), conferred by variation in the CARD14 gene (607211) on 17q; 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, and PSORS12 (612950) on 20q13. PSORS13 (614070) is associated with the TRAF3IP2 gene (607043) on chromosome 6q21. An additional putative psoriasis candidate locus has been reported on 20p (Nair et al., 1997).
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 ... - 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) 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 dbSNP rs10484554A, also known as CW*0602. When compared with the most protective 2-locus genotype, homozygosity for the A allele at the HLAC SNP dbSNP rs10484554 and the A allele at ERAP1 SNP dbSNP 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 dbSNP 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 dbSNP 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.