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.
We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti-TNF-α) and ustekinumab (anti-IL-12/23).
We investigated its role in susceptibility to psoriasis, the relevance of possibly other disease-causing variants, and interdependency of the major risk factor for psoriasis at PSORS1.
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.
We have investigated the association and possible functional role of non-synonymous SNPs at different exons of ERAP1 (rs26653: Arg127Pro, rs30187: rs30187" genes_norm="51752">Lys528Arg and rs27044: rs27044" genes_norm="51752">Gln730Glu) and their interactions with HLA-C∗06 in psoriasis.
We genotyped 142 patients and 160 healthy volunteers to evaluate the possible relationship between susceptibility to psoriasis and the HLA-C*0602 allele and polymorphisms in the TNF, IL12B, and IL23R genes.
We further identified multiple independent new susceptibility loci in HLA-C, HLA-B, HLA-DPB1 and BTNL2 and an intergenic variant, rs118179173, associated with psoriasis and confirmed the well-established risk allele HLA-C*06:02.
We found an association between HLA-Cw*06 and PsA namely PsA with psoriasis type I (age of psoriasis onset before 40 years) compared to healthy individuals (P (corrected) < 0.05, OR 2.56, CI 95% 1.33-4.76 and P (corrected) = 0.01, OR 3.03, CI 95% 1.53-5.88, respectively).
We first demonstrate hypermethylation of HLA-C gene in psoriatic epidermis, suggesting that HLA-C hypermethylation may be an epigenetic marker in psoriasis.
We demonstrate utility of the method through analysis of a genome-wide association study for psoriasis where there is a known classical HLA risk allele (HLA-C*06:02).
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).
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.
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.
Very recent data strongly indicate that HLA-Cw*0602 is the susceptibility allele in this locus, a finding that is consistent with the notion that the pathogenesis of psoriasis involves autoantigen recognition by epidermal CD8+ T lymphocytes.
To investigate the association between smoking and psoriatic arthritis (PsA) among patients with psoriasis and its interaction with the HLA-C*06 allele.
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.
To ascertain whether there are differences in the clinical features and relative risk between HLA-Cw*0602 homozygous and heterozygous psoriasis patients.
Thus, we measured the effect of potential interaction between human leukocyte antigen (HLA)-C, CSTA and D1S236 at PSORS1, PSORS4 and PSORS5, respectively, in the development of psoriasis.
Thus, our findings demonstrate the presence of allele-specific differences in HLA-C expression and indicate that HLA-Cw*0602 is unresponsive to upregulation by key proinflammatory cytokines in psoriasis.
Three risk loci shared with ankylosing spondylitis and psoriasis (the MHC class I region, ERAP1 and IL23R and the MHC class I-ERAP1 interaction), as well as two loci shared with inflammatory bowel disease (IL23R and IL10) implicate shared pathogenic pathways in the spondyloarthritides and Behçet's disease.