Association analysis using refined microsatellite markers localizes a susceptibility locus for psoriasis vulgaris within a 111 kb segment telomeric to the HLA-C gene.

The HLA-Cw6 antigen has been associated with psoriasis vulgaris despite racial and ethnic differences. However, it remains unclear whether it is the HLA-Cw6 antigen itself or a closely linked, hitherto unidentified, locus that predisposes to the disease. Here, in order to map the susceptibility locus for psoriasis vulgaris precisely within the HLA class I region, 11 polymorphic microsatellite markers distributed throughout a 1060 kb segment surrounding the HLA-C locus were subjected to association analysis in Japanese psoriasis vulgaris patients. Statistical analyses of the distribution and deviation from Hardy-Weinberg equilibrium of the allelic frequency at each micro-satellite locus revealed that the pathogenic gene for psoriasis vulgaris is located within a reduced interval of 111 kb spanning 89-200 kb telomeric of the HLA-C gene. In addition to three known genes, POU5F1, TCF19 and S, this 111 kb fragment contains four new, expressed genes identified in the course of our genomic sequencing of the entire HLA class I region. Therefore, these seven genes are the potential candidates for susceptibility to psoriasis vulgaris.

New polymorphic microsatellite markers in the human MHC class I region.

The human major histocompatibility complex (MHC) class I region is believed to contain a large number of genes encoding susceptible factors for diseases such as Behcet's disease, Graves disease and psoriasis vulgaris. To identify the causative genes of those diseases, we have conducted large-scale genomic sequencing and determined the 1.8 Mb entire HLA class I region from the MICB gene to the HLA-F gene. During the course of genomic sequencing, a total of 731 microsatellite sequences with dinucleotide to pentanucleotide repeats were found in this region. Previously, we reported that 26 microsatellites between MICB and S on the most centromeric side of the class I region, and between HSR1 and HLA-92/L in the midst of the class I region were highly polymorphic, and served as excellent genetic markers. In this paper, in order to fill the gaps with no known polymorphic microsatellites available in the HLA class I region, 12 new polymorphic microsatellite markers were recruited from the 1.8 Mb region including the remaining class I segments, namely between S and HSR1, and between HLA-92/L and HLA-F The average number of alleles at these new microsatellite loci was 8.2 with a polymorphism content value (PIC) of 0.63. These 38 markers in total almost uniformly interspersed in the HLA class I region will enable us to search precisely for the location of disease susceptible loci within the HLA class I region by association and for linkage analyses.