High-need patients with psoriasis had a lower frequency of HLA-Cw*06 but a higher prevalence of HLA-B*46 compared with general patients with psoriasis in our population.
To determine the structural basis of this selectivity, we determined crystal structures of HLA-C*06:02 in complex with two self-peptides (ARTELYRSL and ARFNDLRFV) and an analogue of a melanocyte autoantigen (ADAMTSL5, VRSRR-abu-LRL) implicated in psoriasis.
Regression analysis showed that the LoPsA group at presentation was characterized by: less males (OR 0.4, p = 0.001), less HLA-C*06 (OR 0.3, p = 0.005), longer psoriasis duration (OR 1.04, p = 0.0005), higher BMI (OR 1.1, p = 0.005) and higher modified Steinbrocker score (mSS) (OR 1.1, p = 0.005).
HLA-Cw*06 and HLA-DRB1*07 are associated with patients with PsA having type I psoriasis, suggesting that the primary association is with age of onset of psoriasis.
Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49-72 kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33.
These results suggest that a major psoriasis susceptibility gene is likely to be located within a region of 150 kb telomeric to HLA-C and centromeric to the CDSN gene.
IFNs are important initiators/regulators of inflammation that among other things can affect the expression of the main genetic determinant in psoriasis, namely HLA-C. Externally administered IFN-alpha, as in patients treated for viral infections, and IFN-alpha produced by plasmacytoid dendritic cells is a known trigger of psoriasis.
Comparison of HLA-B and HLA-C regions in psoriatic arthritis with those in psoriasis without joint involvement demonstrates significant differences, such that psoriatic arthritis cannot be viewed simply as a subset of genetically homogeneous psoriasis.
It has been recently suggested by microsatellite mapping that a real susceptible gene for psoriasis resides in the approximately 100-kb genomic region telomeric of the HLA-C gene.
In this retrospective multicentre study we reviewed data of 255 patients with psoriasis genotyped for HLA-C*06 who started ustekinumab treatment between January 2014 and March 2015.
In patients with PsA expressing the HLA-C*06 antigen, the latency between the onset of psoriasis and onset of joint symptoms is longer than in those without this marker.
We confirmed that HLA-Cw*0602 positive patients have younger age of onset (17.5 vs 24.3 years, P<10(-10)), higher incidence of guttate and the eruptive type of psoriasis (P<0.0001), more frequent exacerbations with throat infections (P=0.01), higher incidence of the Koebner's phenomenon (P=0.01), and more extensive disease (P=0.03).
Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A<sup>*</sup>29:02), ankylosing spondylitis (HLA-B<sup>*</sup>27), Behçet's disease (HLA-B<sup>*</sup>51), and psoriasis (HLA-C<sup>*</sup>06:02).
PSORS1-PSORS9 have been confirmed as psoriasis susceptibility loci in independent genetic studies on predominantly Caucasian populations, with psoriasis susceptibility loci (PSORS1, PSORS9) and additional loci at 9q33-34 and 2p22.3-11.2 reported in Han Chinese patients.
We concluded that psoriasis is based on a melanocyte-specific immune response and that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway.
Expanding on the previously reported experience with this patient, we conclude that HLA-C*18:01 probably indicates a severe, recalcitrant, multidrug-resistant psoriasis phenotype for which proper therapy remains to be identified.
While the previously reported association between TNF*-238A and psoriasis seems to primarily reflect LD with PSORS1, TNF*-857T may represent a risk factor for PsA that is independent of the PSORS1 allele.