(ii) Results show that Ala-73 on HLA-C molecules is increased in frequency in psoriasis, but results observed show an association more subtle than previously thought, with HLA-Cw*0602 playing the major role.
We also conclude that the HLA-B17 allele, which is strongly associated with psoriasis, is unlikely itself to contribute directly to psoriasis susceptibility; rather, the HLA-B locus is probably tightly linked to the PSORS1 locus.
By applying the transmission/disequilibrium test (TDT) and parametric linkage analysis, we found evidence for linkage of psoriasis to HLA-C, -B, -DR, and -DQ, with HLA-B and -C yielding the most-significant results.
Eleven of 14 patients (79%) with psoriasis carried the HLA-Cw*0602 allele compared with 24.5% of those without psoriasis (odds ratio = 11.31; 95% confidence limits 2.73 to 65.36; P = 0.0001).
The strong association found here, coupled with the biological involvement of the MHC S gene product corneodesmosin in skin physiology, implicates this locus (or a haplotype across HLA-C and MHC S ) in the impaired desquamation characteristic of psoriasis.
Amongst patients with psoriatic arthritis, those who carried the HLA-Cw*0602 allele had a significantly earlier mean age of onset of their psoriasis (p = 0.003).
Hence these studies contribute to the refinement of the localization of a major psoriasis susceptibility gene and place the critical region near to HLA-C.
Our results suggest that the MICA 5.1 allele might be a genetic marker related to the early onset of psoriasis and play a secondary role to the HLA-Cw*0602 gene or an unknown causative gene closely linked to HLA-Cw*0602 in the genetic susceptibility to psoriasis.
The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its reportedly exclusive expression in differentiating keratinocytes.
An association study of the new HCR polymorphisms and the previously suggested susceptibility alleles HLA-Cw*0602 and corneodesmosin allele 5 (CD*5) with psoriasis revealed a specific HCR variant associated with psoriasis susceptibility.
These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.
The method is applied to PSORS1, a locus within the major histocompatibility complex (MHC) for which linkage and linkage disequilibrium with psoriasis has already been demonstrated.