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Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus
Kati Asumalahti1, Colin Veal, Tarja Laitinen
1Department of Medical Genetics and Finnish Genome Center, University of Helsinki, 00014 Helsinki, Finland.
Insights
The HCR*WWCC allele, a variant of the HCR gene, is strongly associated with psoriasis. This finding suggests HCR plays a key role in psoriasis development, potentially affecting skin cell growth.
Area of Science:
- Genetics
- Dermatology
- Molecular Biology
Background:
- The PSORS1 locus, near HLA-C, is the primary genetic determinant for psoriasis.
- Identifying specific genes within PSORS1 is crucial for understanding psoriasis pathogenesis.
Purpose of the Study:
- To investigate the role of the HCR gene at the PSORS1 locus in psoriasis susceptibility.
- To determine if specific HCR gene variants are associated with psoriasis.
Main Methods:
- Genotyping of 419 families across six populations to identify HCR gene variants.
- Association analysis of HCR alleles with psoriasis and HLA-Cw6.
- Structural prediction of HCR protein variants.
- Analysis of HCR protein expression in psoriatic skin.
Main Results:
- A conserved HCR allele, HCR*WWCC, showed a highly significant association with psoriasis across all populations.
- HCR*WWCC was in strong linkage disequilibrium with the HLA-Cw6 allele.
- The HCR*WWCC variant was predicted to alter HCR protein secondary structure.
- Differential HCR protein expression was observed in lesional psoriatic skin compared to normal skin.
Conclusions:
- The HCR*WWCC allele is a major genetic determinant for psoriasis.
- The mechanism likely involves HCR impacting keratinocyte proliferation.
- HCR is a key genetic factor contributing to psoriasis susceptibility.
Abstract:
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. Because of strong linkage disequilibrium between HLA-Cw6 and HCR*WWCC, the two genes could not be genetically distinguished by this sample size. However, the variant HCR allele was predicted to differ in secondary structure from the wild-type protein. HCR protein expression in lesional psoriatic skin differed considerably from that observed in normal skin. These results provide strong evidence for the HCR*WWCC allele as a major genetic determinant for psoriasis, probably by a mechanism impacting on keratinocyte proliferation.