The PSORS1 locus in the major histocompatibility complex region on chromosome 6p21.3 contains a major predisposing factor for psoriasis for which several candidate genes have been tested. The analyses are complicated ...The PSORS1 locus in the major histocompatibility complex region on chromosome 6p21.3 contains a major predisposing factor for psoriasis for which several candidate genes have been tested. The analyses are complicated by strong linkage disequilibrium in the region and the complex genetic background of psoriasis. In the search for an alternative to HLA-C we have identified a novel gene, PSORS1C3, and characterized it with regard to psoriasis. PSORSC3 is located approximately 7 kb centromeric to POU5F1. A putative protein of 58 amino acids was predicted and expression was detected in both normal and psoriasis skin. Sequencing of the coding region revealed a total of 11 single nucleotide polymorphisms. When comparing the frequencies of PSORS1C3 variants in a case- control material in the Swedish population,three single nucleotide polymorphisms displayed significant association with psoriasis. This association appeared to be HLA-Cw.0602- dependent due to linkage disequilibrium, thus HLA- C remains the strongest associating factor in the region.展开更多
Human leukocyte antigen(HLA)-Cw6 has long been associated with psoriasis, and PSORS1 (psoriasis susceptibility 1), a major gene for psoriasis susceptibility, has been mapped to its vicinity. A previous analysis identi...Human leukocyte antigen(HLA)-Cw6 has long been associated with psoriasis, and PSORS1 (psoriasis susceptibility 1), a major gene for psoriasis susceptibility, has been mapped to its vicinity. A previous analysis identified multiple risk haplotypes carrying HLA-Cw6 and one haplotype (cluster 17, HLA-Cw8-B65) that appeared to carry risk for psoriasis but did not carry HLACw6. This haplotype was very similar to other risk haplotypes for at least 60 kb telomeric to HLA-C, suggesting identity by descent with the remaining risk chromosomes. The association, however, between psoriasis and this haplotype as assessed by the transmission/disequilibrium test (TDT) was of borderline significance (p-value 0.048). In order to better assess the risk associated with cluster 17, a multicenter collaboration typed additional subjects for a single marker (M6S161) for which one allele (249 bp) was found only on cluster 17. The new sample included 1275 pedigrees as well as 300 cases and 913 controls. Transmission of this allele to affected individuals was examined using the TDT and the pedigree disequilibrium test (PDT), and case-control samples were analyzed by a trend test across genotype categories. By all methods, the newly acquired genotypes failed to confirm the association originally reported, despite adequate power. In contrast, the 248 bp allele, which is found on all HLA-Cw6-positive risk haplotypes as well as several non-risk haplotypes, shows significant excess transmission for all cohorts. Taken together, these results indicate that cluster 17 does not carry a psoriasis-susceptibility allele, and expand the PSORS1 risk interval to approximately 300 kb.展开更多
Background:Although genetic analyses have identified the HLA-Cw0602 allele as the major risk allele for chronic plaque psoriasis in various ethnic groups, it has been proposed that the association of Cw0602 is due...Background:Although genetic analyses have identified the HLA-Cw0602 allele as the major risk allele for chronic plaque psoriasis in various ethnic groups, it has been proposed that the association of Cw0602 is due to linkage disequilibrium and that other nearby genes are involved in susceptibility to psoriasis. The psoriasis susceptibility 1 candidate 1 (PSORS1C1, formerly SEEK1) gene, located 127 kb telomeric to the HLAC locus, is considered to be one of the potential candidate genes of psoriasis. Up to the present, no association study of the PSORS1C1 gene has been conducted on Chinese patients with psoriasis. Objectives:We aimed to determine whether the genetic polymorphisms of the PSORS1C1 gene were associated with an increased risk of psoriasis in Chinese patients. Methods:We investigated the PSORS1C1 gene for disease association by direct sequencing of the PSORS1C1 gene in 143 Chinese patients with chronic plaque psoriasis and 188 control subjects. Genotyping for HLA-Cw0602 and the α-helix coiled-coil rod homologue (C6orf18, formerly HCR) gene was also carried out using a sequence-based typing method. Results:We identified 10 single nucleotide polymorphisms (SNPs) on the PSORS1C1 gene in our subjects; four of these SNPs cause amino acid change. We also detected poly(C) repeat variants from nucleotide positions 386-392 (poly(C) 6-8). The poly(C)repeat polymorphisms cause a frame shift mutation. Another poly(C) repeat variant was also found at nucleotide positions 748-751. No significantly different allelic distributions of the PSORS1C1 SNPs or poly(C) repeat polymorphisms could be found between the patients with chronic plaque psoriasis and controls after correction for multiple testing. However, a significant in crease of the Cw0602 allele and tryptophan-tryptophan allele of the C6orf18 gene (HCRWW) was found in patients with early onset psoriasis (21.9%vs. 4.8%, P < 10-7). Haplotype-based association analysis also showed a susceptibility haplotype carrying Cw0602 and HCRWW alleles in early onset Chinese patients. Conclusions:Our results indicate that the PSORS1C1 gene might not play an important role in the causation of chronic plaque psoriasis in Chinese people .展开更多
Background: Besides the HLA-Cw0602 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 an...Background: Besides the HLA-Cw0602 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 CDSN971T allele, CDSNTTC (619T-1236T-1243C) and CDSN5 (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-Cw0602, α-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 PSORS1C3582A 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, Pc =0.0000 072). The frequencies of CDSNTTC and CDSN971T were also significantly increased in patients with early-onset psoriasis vulgaris. Moreover, PSORS1C3582A, SNP n.9C,Cw0602 and HCRWWCC were in near complete linkage disequilibrium(LD) with each other; in contrast, the LD with the CDSN gene was not so strong. SNP n.9C-Cw0602-PSORS1C3582A-HCRWWCC was a major susceptibility haplotype in patients with early-onset psoriasis vulgaris (P < 10-7) and this risk haplotype also carried CDSNTTC and CDSN971T. Conclusions: The PSORS1C3 and CDSN genes are important psoriasis susceptibility genes in Chinese patients with psoriasis vulgaris.展开更多
文摘The PSORS1 locus in the major histocompatibility complex region on chromosome 6p21.3 contains a major predisposing factor for psoriasis for which several candidate genes have been tested. The analyses are complicated by strong linkage disequilibrium in the region and the complex genetic background of psoriasis. In the search for an alternative to HLA-C we have identified a novel gene, PSORS1C3, and characterized it with regard to psoriasis. PSORSC3 is located approximately 7 kb centromeric to POU5F1. A putative protein of 58 amino acids was predicted and expression was detected in both normal and psoriasis skin. Sequencing of the coding region revealed a total of 11 single nucleotide polymorphisms. When comparing the frequencies of PSORS1C3 variants in a case- control material in the Swedish population,three single nucleotide polymorphisms displayed significant association with psoriasis. This association appeared to be HLA-Cw.0602- dependent due to linkage disequilibrium, thus HLA- C remains the strongest associating factor in the region.
文摘Human leukocyte antigen(HLA)-Cw6 has long been associated with psoriasis, and PSORS1 (psoriasis susceptibility 1), a major gene for psoriasis susceptibility, has been mapped to its vicinity. A previous analysis identified multiple risk haplotypes carrying HLA-Cw6 and one haplotype (cluster 17, HLA-Cw8-B65) that appeared to carry risk for psoriasis but did not carry HLACw6. This haplotype was very similar to other risk haplotypes for at least 60 kb telomeric to HLA-C, suggesting identity by descent with the remaining risk chromosomes. The association, however, between psoriasis and this haplotype as assessed by the transmission/disequilibrium test (TDT) was of borderline significance (p-value 0.048). In order to better assess the risk associated with cluster 17, a multicenter collaboration typed additional subjects for a single marker (M6S161) for which one allele (249 bp) was found only on cluster 17. The new sample included 1275 pedigrees as well as 300 cases and 913 controls. Transmission of this allele to affected individuals was examined using the TDT and the pedigree disequilibrium test (PDT), and case-control samples were analyzed by a trend test across genotype categories. By all methods, the newly acquired genotypes failed to confirm the association originally reported, despite adequate power. In contrast, the 248 bp allele, which is found on all HLA-Cw6-positive risk haplotypes as well as several non-risk haplotypes, shows significant excess transmission for all cohorts. Taken together, these results indicate that cluster 17 does not carry a psoriasis-susceptibility allele, and expand the PSORS1 risk interval to approximately 300 kb.
文摘Background:Although genetic analyses have identified the HLA-Cw0602 allele as the major risk allele for chronic plaque psoriasis in various ethnic groups, it has been proposed that the association of Cw0602 is due to linkage disequilibrium and that other nearby genes are involved in susceptibility to psoriasis. The psoriasis susceptibility 1 candidate 1 (PSORS1C1, formerly SEEK1) gene, located 127 kb telomeric to the HLAC locus, is considered to be one of the potential candidate genes of psoriasis. Up to the present, no association study of the PSORS1C1 gene has been conducted on Chinese patients with psoriasis. Objectives:We aimed to determine whether the genetic polymorphisms of the PSORS1C1 gene were associated with an increased risk of psoriasis in Chinese patients. Methods:We investigated the PSORS1C1 gene for disease association by direct sequencing of the PSORS1C1 gene in 143 Chinese patients with chronic plaque psoriasis and 188 control subjects. Genotyping for HLA-Cw0602 and the α-helix coiled-coil rod homologue (C6orf18, formerly HCR) gene was also carried out using a sequence-based typing method. Results:We identified 10 single nucleotide polymorphisms (SNPs) on the PSORS1C1 gene in our subjects; four of these SNPs cause amino acid change. We also detected poly(C) repeat variants from nucleotide positions 386-392 (poly(C) 6-8). The poly(C)repeat polymorphisms cause a frame shift mutation. Another poly(C) repeat variant was also found at nucleotide positions 748-751. No significantly different allelic distributions of the PSORS1C1 SNPs or poly(C) repeat polymorphisms could be found between the patients with chronic plaque psoriasis and controls after correction for multiple testing. However, a significant in crease of the Cw0602 allele and tryptophan-tryptophan allele of the C6orf18 gene (HCRWW) was found in patients with early onset psoriasis (21.9%vs. 4.8%, P < 10-7). Haplotype-based association analysis also showed a susceptibility haplotype carrying Cw0602 and HCRWW alleles in early onset Chinese patients. Conclusions:Our results indicate that the PSORS1C1 gene might not play an important role in the causation of chronic plaque psoriasis in Chinese people .
文摘Background: Besides the HLA-Cw0602 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 CDSN971T allele, CDSNTTC (619T-1236T-1243C) and CDSN5 (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-Cw0602, α-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 PSORS1C3582A 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, Pc =0.0000 072). The frequencies of CDSNTTC and CDSN971T were also significantly increased in patients with early-onset psoriasis vulgaris. Moreover, PSORS1C3582A, SNP n.9C,Cw0602 and HCRWWCC were in near complete linkage disequilibrium(LD) with each other; in contrast, the LD with the CDSN gene was not so strong. SNP n.9C-Cw0602-PSORS1C3582A-HCRWWCC was a major susceptibility haplotype in patients with early-onset psoriasis vulgaris (P < 10-7) and this risk haplotype also carried CDSNTTC and CDSN971T. Conclusions: The PSORS1C3 and CDSN genes are important psoriasis susceptibility genes in Chinese patients with psoriasis vulgaris.
