Psoriasis vulgaris is associated with the HLA-Cw6 and Cw7 antigens. We have previously narrowed down the critical region most likely to contain the psoriasis vulgaris gene to 111 kb spanning 89 kb to 200 kb telomeric of the HLA-C locus by microsatellite mapping. This segment includes three known genes (POU5F1, SC1 and S) and four new expressed genes. Among them, SC1 (TCF19) is the cell growth regulated gene possibly with trans-activator activity. Since psoriasis vulgaris is a common skin disorder characterized by hyperproliferation of epidermal cells, it is tempting to speculate that the SCI gene is one of the strong candidate genes responsible for the development of psoriasis vulgaris. Here, we investigated genetic polymorphisms in the SC1 gene by direct DNA sequencing and polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) techniques. Three single nucleotide polymorphisms in exon 2, two of which are accompanied by amino-acid substitutions, were identified. Further, one 4-bp deletion polymorphism was detected around the acceptor site of the lariat-shaped structure necessary for RNA splicing in intron 2. No significant difference in the dimorphic or haplotypic distribution at these four polymorphic sites was observed between the patients with psoriasis vulgaris and healthy controls. This suggests that the susceptible gene for psoriasis vulgaris is not the SC1 gene itself, although a unique homozygous haplotype was identified in the patients.

Polymorphisms of the 5'-flanking promoter/enhancer region of the TNAFA gene were determined in 80 Japanese patients with pulmoplantar pustulosis (PPP). The 5'-flanking region of the TNFA gene from -1107 to 66 was amplified by polymerase chain reaction (PCR) method. Nucleotide sequencing data from the PCR products revealed that 5 single nucleotide polymorphisms at position 1031, -863, -857, -307 and -237. None of the nucleotide substitutions were significantly increased in PPP patients when compared with those in controls. To clarify the linkage among the neighboring genetic marker, we analyzed the association between the polymorphisms in the TNFA promoter region and the NcoI polymorphism in the first intron of the TNFB gene as well as HLA-DR9. The genotype at 1031C is strongly associated with TNFB1 and negatively associated with TNFB2 which is reported to be associated with PPP. These data indicate that TNFA gene centromeric to TNFB is not associated with PPP and the susceptible gene of PPP is located between TNFB and HLA-B.

We investigated the allelic distributions of single nucleotide polymorphisms (SNPs) of the TNFA, TNFB and IKBL genes, 3 microsatellites within the tumor necrosis factor (TNF) region of HLA locus, and the HLA phenotypes as well as the TLR4 gene in Chromosome 9 in 26 healthy Caucasian volunteers. These individuals were also assessed as ultraviolet B (UVB)-susceptible (S) or UVB-resistant (R). Our results identified 12 UVB-S and 14 UVB-R individuals. Attempts to correlate particular HLA-A, -B, -C, and -DR antigens with the UVB phenotypes failed. Similarly, attempts to correlate SNP at the NcoI-RFLP within intron 1 of the TNFB, IKBL and TLR4 gene with UVB phenotypes also failed. However, microsatellite analyses of TNFa, TNFc, and TNFd markers revealed a significant increase in the frequencies of TNFa2 in UVB-S individuals (P=0.00032) and of TNFd3 in UVB-R individuals (P=0.012). Moreover, DNA sequencing analyses of 5 SNPs of the TNFA promoter region revealed a significant increase in the frequency of the allele B of the TNFA gene (TNFApB) representing the nucleotide A at position -863 and C at position -1031 (P=0.015). Since it is known that TNFa2 and TNFApB is a high TNF-alpha responder, whereas TNFd3 is a TNF-alpha low responder, we propose that the TNF region of HLA contains polymorphic genes that confer susceptibility and resistance to the deleterious effects of UVB radiation on the induction of contact hypersensitivity. This proposal is consistent with previous reports that a unique microsatellite region of the Tnfa gene in mice contains alleles that dictate the UVB-dependent phenotypes in mice, and implicate TNF-alpha as the primary mediator of the immune-damaging effects of UVB radiation.

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We analysed a polymorphism of the interleukin (IL)-1 receptor antagonist (IL1RN) gene in 93 Japanese patients with palmoplantar pustulosis (PPP). None of the IL1RN alleles was significantly increased in the patients compared with controls. Because PPP has been reported to be associated with the tumour necrosis factor (TNF) region, we examined the association between the TNF and IL1RN genes. There was a difference in IL1RN*2 positivity between patients with and without the AA genotype of the TNF gene. In contrast, such a difference was not found in controls. These data indicate a possible epistatic effect between TNF and IL1RN linked genes for susceptibility to the pathogenesis of PPP.