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.
These findings suggest locus heterogeneity at PSORS1 (psoriasis susceptibility 1), the major psoriasis susceptibility locus in the MHC, with HLA-Cw6 imparting risk in both Caucasians and Asians, and an allele other than HLA-Cw1 on the HLA-Cw1-B46 haplotype acting as an additional risk variant in East Asians.
The psoriasis susceptibility locus 1 (PSORS1) mutation is assumed to reside within a region around human leukocyte antigen-C spanning 250 kb, termed risk haplotype (RH) 1/2.
Initial analysis of these data revealed and/or confirmed association between psoriasis and seven genetic loci-HLA-C, IL12B, IL23R, IL23A, IL4/IL13, TNFAIP3, and TNIP1-and ongoing studies are revealing additional loci.
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 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.
Paediatric-onset psoriasis showed a significant association with single nucleotide polymorphisms in the ERAP1 (P = 0.042) and IL23R loci (P = 0.042), LCE3C_LCE3B-del (P = 0.003) and HLA-C*06 (P = 1.72 × 10(-19)) when compared with the control group.
For comparison we also genotyped the microsatellite tn62 as a reference marker of the major psoriasis susceptibility locus on chromosome 6p21 (PSORS1).
Additionally, we showed a HLA-C*06:02-independent gender-related effect of the rs887466A allele which was protective against psoriasis in males (OR = 0.61, p = 9.2e-005), but not in females (p = 0.66).
To ascertain whether there are differences in the clinical features and relative risk between HLA-Cw*0602 homozygous and heterozygous psoriasis patients.
These data suggest that the study cohort may include a number of subjects who harbor PSORS1 predisposition to early-onset psoriasis and yet do not present with disease by the age of 40 y.
Predisposition to psoriasis is known to be affected by genetic variation in HLA-C, IL12B, and IL23R, and although other psoriasis-associated variants have been identified, incontrovertible statistical evidence for these markers has not yet been obtained.
Notwithstanding these difficulties, genome-wide scans for psoriasis susceptibility have generated robust evidence for a major locus lying within the major histocompatibility complex (PSORS1, Psoriasis Susceptibility 1), on the short arm of chromosome 6.
A possible reason for the erratic replication of findings could be the large effect of the PSORS1 locus (6p21) masking the effect of other loci involved in psoriasis.
Further analysis with imputed classical HLA alleles suggested the known psoriasis risk allele <i>HLA-C*06:02</i> as a risk factor for tonsillitis (<i>P</i> = 4.8 × 10<sup>-4</sup>; OR, 2.3).