Transgenic mouse models support HCR as an effector gene in the PSORS1 locus.

Genetic susceptibility for psoriasis is regulated to the greatest extent by the PSORS1 locus. Three psoriasis-associated susceptibility alleles have been identified within it, namely, HLACw6, HCR*WWCC and CDSN*5, but strong linkage disequilibrium between them has made it difficult to distinguish their individual genetic effects, and animal models to study their effects are not known. To study the function of HCR, we engineered transgenic mice with either a non-risk allele of HCR or the HCR*WWCC risk allele under the control of the cytokeratin-14 promoter.

HCR, a candidate gene for psoriasis, is expressed differently in psoriasis and other hyperproliferative skin disorders and is downregulated by interferon-gamma in keratinocytes.

We have previously shown that HCR is a good candidate gene for psoriasis based on its location in the PSORS1 locus, predicted secondary structure change of the associated allele, and expression pattern. To understand better the function of HCR, we studied how HCR expression is altered in hyperproliferative skin diseases other than psoriasis and in cancers. We examined also its regulation by different cytokines, growth factors, and antipsoriatic agents using quantitative RT-PCR (TaqMan) analysis and its location by immunostaining of keratinocyte cultures.

Psoriasis susceptibility locus on 18p revealed by genome scan in Finnish families not associated with PSORS1.

The major susceptibility locus for psoriasis, PSORS1, resides on chromosome 6p and includes the candidate genes HLA-C, HCR, and CDSN. Based on a nationwide collection of psoriasis patients and genotyping for the PSORS1 susceptibility haplotype, we selected for a genome scan nine families who do not show association with PSORS1 to more easily detect minor loci for psoriasis susceptibility. In the genome scan, five loci gave initial evidence of linkage and were studied with a denser marker map.

Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis.

The PSORS1 locus in the major histocompatibility complex region is the major genetic determinant for psoriasis vulgaris. Within the PSORS1 region reside at least three potential candidate genes for psoriasis susceptibility. Specific allelic variants of the genes HLA-Cw*6, HCR*WWCC, and CDSN*5 are strongly associated with psoriasis vulgaris and are in strong linkage disequilibrium with each other.

Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus.

PSORS1, near HLA-C, is the major genetic determinant of psoriasis. We present genetic and structural evidence suggesting a major role for the HCR gene at the PSORS1 locus. Genotyping of 419 families from six populations revealed that coding single-nucleotide polymorphisms of HCR formed a conserved allele HCR*WWCC that associated highly significantly with psoriasis and with the HLA-Cw6 allele in all populations.