Deletion of the late cornified envelope genes LCE3C and LCE3B is associated with psoriasis in a Chinese population

A common deletion comprising LCE3B and LCE3C, members of the late cornified envelope (LCE) gene cluster, has been shown to be significantly associated with psoriasis in several Caucasian populations. The expression of LCE can be induced by skin barrier disruption, leading to psoriatic lesions. To identify whether deletion of genes in the LCE region is a genetic risk factor in the pathogenesis of psoriasis, we genotyped the LCE3C and LCE3B deletion and single-nucleotide polymorphism rs4112788, which is in strong linkage disequilibrium with the LCE gene cluster, via direct sequencing in 468 psoriasis patients and 768 controls in a Chinese population. We found that deletion of the two LCE genes was associated with psoriasis (odds ratio=1.917; 95% confidence interval=1.291-2.847, P=0.001), a conclusion that was similar to that of another independent Chinese cohort study. The deletion was not significantly associated with the age of disease onset, and there was no significant epistatic interaction between deletion and PSORS1 risk allele on 6p21.3. Our study confirms an association between the deletion of LCE3C and LCE3B and psoriasis in a Chinese population.     

Deletion of LCE3C and LCE3B genes is associated with psoriasis in a northern Chinese population

Background It has been shown that a deletion in the late cornified envelope (LCE) gene cluster (LCE3C_LCE3B‐del) is associated with susceptibility to psoriasis in European populations. However, the relationship remains unclear in a northern Chinese population. Objectives The aim of the present study was to clarify this association in this population. Methods In total, 970 patients with psoriasis and 1064 healthy controls were recruited and a polymerase chain reaction assay was used to determine the frequency of this deletion. The effect of this deletion on susceptibility to psoriasis was assessed using SPSS software and the PLINK software package. Results The frequency of the LCE3C_LCE3B‐del differed significantly between patients and healthy controls. In subgroup analysis, the distribution was significantly different between patients with a positive family history of psoriasis and controls, as well as between patients with early‐onset psoriasis and controls. Conclusions The findings indicate that the LCE3C_LCE3B‐del is an important risk factor in the pathogenesis of psoriasis and that the LCE3C_LCE3B‐del does not show an epistatic effect with the HLA‐Cw6 allele on susceptibility to psoriasis in the northern Chinese population.     

Association analysis of LCE3C–LCE3B deletion in Tunisian psoriatic population

An association between a common deletion comprising the late cornified envelope LCE3B and LCE3C genes (LCE3C_LCE3B-del) and psoriasis has been reported in Caucasian and Asian populations. To investigate whether this deletion plays a role in the genetic of psoriasis in Tunisian population, we determined the LCE3C_LCE3B-del genotype in 180 Ps patients and 208 healthy controls from different regions of Tunisia. The LCE3B and LCE3C gene variant was determined in the patients through PCR amplification and the SPSS software package. The frequency of the LCE3C_LCE3B-del was similar between patients and healthy controls. Subanalyses by family history revealed that the frequency of LCE3C_LCE3B-del was significantly higher in patients with a positive family history than in control individuals, as well as in individuals with a positive family history versus those without in the case cohort. However, no significant difference was observed between psoriatic patients with no family history and controls. We also evaluated the relationship between LCE3C_LCE3B-del and PSORS1. No significant epistatic effect was observed suggesting that there was no significant epistasis of the two loci in the Tunisian population. Our findings indicate that the LCE3C_LCE3B-del might play a role in familial psoriasis in the Tunisian population.     

Analysis of protein–protein interaction between late cornified envelope proteins and corneodesmosin

Deletion of two members of the late cornified envelope (LCE) family, LCE3B and LCE3C (LCE3C_LCE3B‐del), has been identified as risk factor for psoriasis with a possible role in skin barrier function. Moreover, genetic interaction between LCE3C_LCE3B‐del and HLA‐C*06, located in the psoriasis susceptibility regions 4 and 1 (PSORS4 and 1), has been reported in several populations. Because of high linkage disequilibrium between the PSORS1 genes HLA‐C*06 and corneodesmosin (CDSN), both genes are potentially involved in psoriasis. As corneodesmosin and LCE proteins are both constituents of the stratum corneum, we investigated potential direct protein–protein interactions between six LCE proteins and two corneodesmosin sequence variants. Partial colocalization of LCE2 and CDSN was observed in normal and psoriasis skin using immunofluorescence microscopy. Co‐expression of eCFP‐LCE and mRFP‐CDSN proteins in COS‐1 cells and human adult keratinocytes, and GST pull‐down results did not provide evidence for direct interactions between LCE proteins and CDSN variants.     

New psoriasis susceptibility genes: momentum for skin-barrier disruption

The epidermal differentiation complex gene cluster is on chromosome region 1q21.3, where the PSORS4 locus was mapped. A common deletion of two LCE genes (LCE3C_LCE3B-del) was associated with psoriasis. Individuals homozygous for the deletion have an impaired response of the skin barrier to exogenous agents, facilitating the systemic skin inflammation characteristic of psoriasis.     

Association of skin barrier genes within the PSORS4 locus is enriched in Singaporean Chinese with early-onset psoriasis

Psoriasis (OMIM#177900) is a common polygenic skin disorder affecting approximately 2% of the northern European population and 0.1% of the Han Chinese. Psoriasis patients suffer from chronic skin inflammation, manifested by erythematous scaly lesions. PSORS1-PSORS9 have been confirmed as psoriasis susceptibility loci in independent genetic studies on predominantly Caucasian populations, with psoriasis susceptibility loci (PSORS1, PSORS9) and additional loci at 9q33-34 and 2p22.3-11.2 reported in Han Chinese patients. In this study, we show the association of PSORS4 with psoriasis in Singaporean Chinese. Dense genotyping of single-nucleotide polymorphism-tagging candidate genes within the epidermal differentiation complex revealed significant association in the proximity of the involucrin gene (IVL); the strongest association was seen in early-onset psoriasis patients (P=0.0014). A follow-up genome-wide association screen localized the psoriasis susceptibility region to approximately 360 kb along chromosome 1 in the vicinity of IVL, small proline-rich region (SPRR) and proline-rich region 9 (PRR9) genes. The study of interactions between the causative variant(s) in this locus will provide insights into a possible role for epidermal barrier formation in the pathogenesis of psoriasis.     

Polymorphisms of the IL12B and IL23R genes are associated with psoriasis

Psoriasis is a common inflammatory and hyperproliferative skin disease with a multifactorial genetic basis. A recent study reported that psoriasis was associated with the IL12B haplotype rs3212227 (3'-untranslated region)-rs6887695 (60 kb, 5') and the IL23R haplotype rs7530511 (L310P)-rs11209026 (Q381R). We examined these four single-nucleotide polymorphisms (SNPs) for association with psoriasis in two groups of North American and German Caucasians: (1) 1,810 cases and 2,522 controls; and (2) 509 pedigrees. Both IL12B markers showed highly significant association with psoriasis in the case-control (rs3212227, odds ratio (OR)=1.62, P=1.7 x 10(-15); rs6887695, OR=1.49, P=2.7 x 10(-15)) and in the family-based analysis (rs3212227, P=2.2 x 10(-3); rs6887695, P=1.7 x 10(-3)). The IL23R SNPs also showed significant association in the cases and controls (rs7530511, OR=1.22, P=3.9 x 10(-3); rs11209026, OR=1.40, P=3.8 x 10(-4)). For both genes, common risk haplotypes were identified whose statistical significance approached (IL23R) or exceeded (IL12B) genome-wide criteria. We found no statistical evidence for interactions of these haplotypes with HLA-Cw6. Our results confirm associations between IL12B and IL23R and psoriasis in Caucasians, and provide a genetic basis for the clinical association between psoriasis and Crohn's disease.     

HLA-DQA1 and DQB1 alleles are associated with genetic susceptibility to psoriasis vulgaris in Chinese Han

BACKGROUND: Psoriasis vulgaris is a chronic skin disorder characterized by infiltration of inflammatory elements, keratinocyte hyperproliferation and altered differentiation. Although the pathogenesis of psoriasis is not fully understood, there is solid evidence of a susceptibility locus in the human leukocyte antigen (HLA) region. OBJECTIVES: To investigate whether HLA-DQA1 and DQB1 alleles are associated with genetic susceptibility to psoriasis vulgaris in Chinese Han. PATIENTS AND METHODS: The polymerase chain reaction-sequence-specific primer (PCR-SSP) method was used to analyse the distribution of HLA-DQA1 and DQB1 alleles in 189 patients with psoriasis and 273 healthy controls. RESULTS: The HLA-DQA1*0104 (OR = 2.33, P = 0.0001154, Pc = 2.0 x 10-3), DQA1*0201 (OR = 3.36, P < 1.0 x 10-7, Pc < 1.0 x 10-6), DQB1*0201 (OR = 1.64, P = 0.0192, Pc > 0.05) and DQB1*0303 (OR = 1.55, P = 0.0377, Pc > 0.05) alleles were more prevalent in patients with psoriasis vulgaris than in controls, and HLA-DQA1*0501 (OR = 0.30, P = 0.0000039, Pc < 4.0 x 10-5) alleles were less prevalent. The HLA-DQA1*0104 (OR = 2.42, P = 0.0001159, Pc < 2.0 x 10-3), DQA1*0201 (OR = 3.74, P < 1.0 x 10-7, Pc < 1.0 x 10-6) and DQA1*0501 (OR = 0.30, P = 0.0000374, Pc < 4.0 x 10-4) alleles were only associated with type I psoriasis. HLA-DQA1*0104 and DQA1*0201 were more prevalent in patients with or without a family history of psoriasis. However, the DQA1*0501 allele was only more prevalent in patients without a family history of psoriasis. CONCLUSION: HLA-DQA1*0104 and DQA1*0201 alleles may be psoriasis susceptibility genes or may be in close linkage with the susceptibility genes. The HLA-DQA1*0501 allele seems to have a protective effect against the development of psoriasis vulgaris in Chinese Han. There may be a difference in genetic background between psoriasis patients with and without a family history of psoriasis.     

Expression profile of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins during skin barrier repair

Background Recent studies have emphasized the importance of heritable and acquired skin barrier abnormalities in common inflammatory diseases such as psoriasis and atopic dermatitis (AD). To date, no comprehensive studies on the effect of experimental barrier disruption on cornified envelope protein expression have been performed. Objectives To analyse the effect of experimental skin barrier disruption on the expression of cornified envelope structural proteins and keratinocyte differentiation‐regulating proteins. Methods We examined mRNA (day 1, 3 and 7) and protein (day 1, 2, 4 and 9) expression levels of structural proteins and regulatory molecules after sodium dodecyl sulphate (SDS) application on normal skin, and tape stripping of uninvolved epidermis of patients with psoriasis and AD and healthy controls. Results Upon tape stripping, several structural molecules were significantly downregulated (at the mRNA level as well as the protein level), including LCE5A, LCE2B, FLG, FLG2 and LOR, whereas others were upregulated: IVL, SPRR1, SPRR2, HRNR and most notably LCE3A. The epidermal crosslinking enzymes TGM1, TGM3 and TGM5 were all upregulated, whereas proteases involved in the desquamation process (CTSV, KLK5 and KLK7) were downregulated or unaffected. Most results were similar in SDS‐instigated irritant contact dermatitis. There was no significant difference in response between normal epidermis and nonlesional skin of patients with psoriasis and AD. Conclusions Skin barrier disruption induces a temporary barrier repair response composed of increased expression of several cornification‐related proteins, and decreased expression of some structural and desquamation‐related proteins.     

Association of the interleukin-10 distal promoter (-2763A/C) polymorphism with late-onset psoriasis

Polymorphisms of the IL-10 promoter have been implicated in the genetic susceptibility to many autoimmune diseases, including psoriasis. Four putative functional single-nucleotide polymorphisms (SNPs) within the interleukin-10 promoter region (-3575T/A, -2763A/C, -1082G/A and -592C/A) were analysed in 139 patients with chronic plaque psoriasis and in 155 unrelated healthy controls from Thailand. There were no significant differences in the allele frequencies of any of the four SNPs between patients with psoriasis and controls. However, the frequency of the -2763A allele was increased in patients with late-onset psoriasis compared with controls and patients with early-onset psoriasis [OR=2.94, 95% CI 1.16-7.39, corrected P value (Pc)=0.04 and OR=3.26, 95% CI 1.13-9.51, Pc=0.048, respectively]. The AAGC (-3575/-2763/-1082/-592) haplotype frequency was higher in late-onset compared with early onset psoriasis (OR=4.37, 95% CI 1.24-15.97, Pc=0.027). This study suggests that the -2763A allele and the extended AAGC haplotype can be used as a genetic marker for susceptibility to late-onset psoriasis in a Thai population.     

Psoriasis vulgaris in Chinese individuals is associated with PSORS1C3 and CDSN genes

BACKGROUND: Besides the HLA-Cw*0602 allele, the psoriasis susceptibility 1 candidate 3 (PSORS1C3) and corneodesmosin (CDSN) genes are two probable psoriasis susceptibility genes in the PSORS1 locus. The -79C, -26C and +246A alleles of the PSORS1C3 gene, the CDSN*971T allele, CDSN*TTC (619T-1236T-1243C) and CDSN*5 (619T-1240G-1243C) are strongly associated with psoriasis in the caucasian population. Until now, no haplotype study of the PSORS1C3 and CDSN genes has been documented in Chinese patients with psoriasis vulgaris. OBJECTIVES: We aimed to determine whether genetic polymorphisms of the PSORS1C3 and CDSN genes were associated with an increased risk of psoriasis vulgaris in Chinese patients in Taiwan. METHODS: We investigated the PSORS1C3 and CDSN genes for disease association by direct sequencing in 178 patients with psoriasis vulgaris and 203 control subjects. Genotyping for HLA-Cw*0602, alpha-helix coiled-coil rod homologue (HCR) gene and single nucleotide polymorphism (SNP) n.9 was also carried out using a sequence-based typing method. RESULTS: The PSORS1C3*582A allele, an SNP in the 3'-untranslated region of the PSORS1C3 gene, was a major psoriasis vulgaris susceptibility allele in the Chinese population, and the association was much stronger in patients with early-onset psoriasis vulgaris (22.3% vs. 6.9%, odds ratio = 3.87, P(c) =0.0000072). The frequencies of CDSN*TTC and CDSN*971T were also significantly increased in patients with early-onset psoriasis vulgaris. Moreover, PSORS1C3*582A, SNP n.9*C, Cw*0602 and HCR*WWCC were in near complete linkage disequilibrium (LD) with each other; in contrast, the LD with the CDSN gene was not so strong. SNP n.9*C-Cw*0602-PSORS1C3*582A-HCR*WWCC was a major susceptibility haplotype in patients with early-onset psoriasis vulgaris (P < 10(-7)) and this risk haplotype also carried CDSN*TTC and CDSN*971T. CONCLUSIONS: The PSORS1C3 and CDSN genes are important psoriasis susceptibility genes in Chinese patients with psoriasis vulgaris.     

Filaggrin null alleles are not associated with psoriasis

Psoriasis is a common skin disease with an etiology consistent with a multifactorial trait. Several psoriasis susceptibility loci are known, a number of which are also implicated in a predisposition to atopic dermatitis (AD), including the epidermal differentiation complex on chromosome 1q21. It has recently been shown in several replicate studies that prevalent null alleles for the filaggrin gene (FLG) on 1q21 are an important genetic factor in AD. Here, we examined the role of these FLG variants in psoriasis using case:control association studies comparing Irish and UK psoriasis cohorts (combined n=691) to ethnically matched populations (combined n=2117). No association was present for the two common European FLG mutations R501X and 2282del4 (combined chi2 P=0.989). In addition, the 3' end of the FLG open-reading frame was sequenced in a number of patients with differing types of psoriasis (plaque, guttate, palmoplantar, and late-onset), which excluded the possibility of a gain-of-function frameshift mutation such as those found in loricrin or certain keratin genes. These data suggest that FLG mutations are unlikely to be involved in genetic susceptibility to psoriasis and implies that there may be within-locus heterogeneity in chromosomal regions involved in both AD and psoriasis.     

Current understanding of human genetics and genetic analysis of psoriasis

During the past 5 years, genome-wide association studies (GWAS), primarily based on single nucleotide polymorphism markers, have identified many loci as potential psoriasis susceptibility regions. These studies appeared to provide strong evidence because the susceptibility genes are involved in the interleukin-23/T-helper 17 axis of psoriasis immunopathogenesis and/or skin barrier functions. However, the "identified" genes only explained a small proportion of psoriasis heritability, although it is known to be comparatively higher than that of other common diseases. GWAS are based on the hypothesis that disease-causing variants are high frequency variants within populations. However, this hypothesis is problematic because deleterious variants such as those predisposing to specific diseases will generally not be maintained by selection pressure throughout human evolution. This issue also affects psoriasis studies. Here, we review the current paradigm shift in human genetic analyses and its implications for detection of psoriasis-causing variants based on linkage analysis and GWAS, except the well-known psoriasis susceptibility locus HLA-C.     

Corneodesmosin (CDSN) gene association with psoriasis vulgaris in Caucasian but not in Japanese populations

PSORS1 on chromosome 6p21.3, which contains the MHC, is a major susceptibility locus for psoriasis vulgaris. This region is characterized by strong linkage disequilibrium and contains the corneodesmosin (CSDN) gene, an attractive candidate for psoriasis susceptibility based on its putative biological function in keratinocyte adhesion, and HLA-Cw6, an established marker for psoriasis susceptibility. We compared two genetically independent populations in order to define the major psoriasis susceptibility gene, a British Caucasian population comprising parent-offspring trios analysed by the transmission disequilibrium test (TDT) and a Japanese case-control population. All individuals were investigated for CDSN polymorphism (+619, +1236, +1240 and +1243) and HLA-C association. Our data confirms strong association with HLA-Cw6 and CDSN allele 5 (+619T, +1240G, +1243C) in the Caucasian cohort (TDT, P = 5.4 x 10(-6)) and in addition defines this region further by identifying a high-risk CDSN haplotype (allele 5 and +1236T, P = 8.5 x 10(-8)). In contrast no association was observed in the Japanese cohort for any HLA-C or CDSN alleles. This data supports a role for the CDSN gene in Caucasian populations with psoriasis. However the lack of association with HLA-Cw6 and CDSN alleles in Japanese psoriasis patients may be because Japanese patients exhibit a form of psoriasis similar to late onset or Type II psoriasis vulgaris in contrast to early onset or Type I disease characterizing our Caucasian population.     

Identification of PTPN22, ST6GAL1 and JAZF1 as psoriasis risk genes demonstrates shared pathogenesis between psoriasis and diabetes

The biological connections between psoriasis and diabetes have been suggested by epidemiological, immunological and genetic studies. To identify additional shared susceptibility loci and investigate shared pathogenesis between these two diseases, we genotyped 89 reported diabetes susceptibility loci in 4456 psoriasis cases and 6027 controls of Chinese population using the MassARRAY system from Sequenom. We discovered three significant associations at rs6679677 on 1p13.2 (P=6.15×10^?5, OR=5.07), rs16861329 on 3q27.3 (P=2.02×10^?4, OR=0.87) and rs849135 on 7p15.1 (P=6.59×10^?9, OR=1.78), which suggested PTPN22, ST6GAL1 and JAZF1 as novel susceptibility genes for psoriasis in Chinese population. Our findings implicated the involvement of T‐cell receptor signalling pathway in the pathogenesis of psoriasis and further confirmed the shared genetic susceptibility between psoriasis and diabetes.     

Deletion of the activating NKG2C receptor and a functional polymorphism in its ligand HLA‐E in psoriasis susceptibility

Psoriasis is an inflammatory, immune‐mediated disease of the skin. Several studies have suggested that natural killer (NK) cells and their receptors may be important for its pathogenesis. Here, we examined whether deletion of the activating natural killer receptor gene NKG2C, which has a frequency of 20% in the European population, was associated with psoriasis susceptibility. The NKG2C deletion and a functional polymorphism in its ligand HLA‐E were genotyped in a Caucasian cohort of 611 psoriasis cases and 493 controls. We found that the NKG2C deletion was significantly increased in cases compared with controls [0.258 vs 0.200, P = 0.0012, OR = 1.43 (1.15–1.79)]. The low‐expressing HLA‐E*01:01 allele was associated with psoriasis (P = 0.0018), although this association was dependent on HLA‐C. Our findings support a potential immunoregulatory role for NK cells in psoriasis and suggest the importance of future studies to investigate the contribution of NK cells and their regulatory receptors to the pathogenesis of psoriasis.     

Macrophage migration inhibitory factor gene polymorphism is associated with psoriasis

Macrophage migration inhibitory factor (MIF), an important pro-inflammatory cytokine, is over-expressed in plaques of psoriasis and increased levels are found in the sera of patients with psoriasis. Promoter polymorphisms of the MIF gene are associated with increased production of MIF and have been found to confer increased risk of susceptibility to chronic inflammatory diseases. We investigated whether there is an association between promoter polymorphisms of the MIF gene and chronic plaque psoriasis. Two hundred and twenty-eight UK caucasian patients with chronic plaque psoriasis, and a control panel of 401 UK caucasian normal volunteers were studied. MIF promoter polymorphisms were genotyped by allelic discrimination, or by a fluorescently labeled primer method, and capillary gel electrophoresis. Carriage of either the MIF-173*C polymorphism or the MIF CATT(7) polymorphism was positively correlated with psoriasis (odds ratios (OR) 1.52 95% confidence intervals (CI) 1.05-2.19 (p=0.024) and OR 1.67 95% CI 1.1-2.5 (p=0.013), respectively. The OR for presence of the CATT(7)-MIF-173(*)C haplotype versus all other haplotypes combined was 1.69 95% CI 1.2-2.5 (p=0.008). The results provide evidence for polymorphisms in the MIF gene, and in particular the CATT(7)-MIF-173(*)C haplotype, being of importance in susceptibility to psoriasis.     

Paediatric-onset psoriasis is associated with ERAP1 and IL23R loci, LCE3C_LCE3B deletion and HLA-C*06

Summary Background Recent genome‐wide association studies have identified several genetic risk factors for psoriasis, but data on their association with age at onset are lacking. Objectives To compare the association between known risk alleles and psoriasis in well‐defined cohorts with paediatric‐ and adult‐onset psoriasis. Methods Based on previous studies we selected seven genes and loci associated with psoriasis. Patients with paediatric‐onset (< 18 years) and adult‐onset psoriasis (≥ 18 years) and controls were genotyped. Genotype frequencies were compared between controls (n = 450) and all cases (n = 217), and between controls and cases stratified for confirmed age at onset (paediatric onset n = 80, adult onset n = 85). Results Paediatric‐onset psoriasis showed a significant association with single nucleotide polymorphisms in the ERAP1 (P = 0·042) and IL23R loci (P = 0·042), LCE3C_LCE3B‐del (P = 0·003) and HLA‐C*06 (P = 1·72 × 10^?19) when compared with the control group. A significant association of these four genes was also demonstrated when all psoriasis cases were compared with controls. In adult‐onset psoriasis a significant association was found for HLA‐C*06 (P = 5·11 × 10^?6) and for LCE3C_LCE3B‐del (P = 0·042). No associations were found for the IFIH1, IL12B and TRAF3IP2 loci. Conclusions Notwithstanding the small cohort sizes, we demonstrated an association with established and recently discovered genetic risk factors in paediatric‐onset psoriasis including genes involved in epidermal barrier function and adaptive immunity. Our data suggest that heritable factors may play a more important role in paediatric‐onset psoriasis than in adult‐onset psoriasis.