HLA-C*06:02-negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio [OR], 2.95; P = 5.85 × 10<sup>-7</sup>), and the difference was greater in HLA-C*06:02-negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10<sup>-5</sup>).
After controlling for the age of psoriasis onset no association of PsA to HLA-C*06:02 (p=0.07) was observed; instead, the most significant association was to amino acid at position 97 of HLA-B (p=1.54×10<sup>-9</sup>) where the presence of asparagine or serine residue increased PsA risk.
Clearly, PsV and PsA are highly variable in terms of their clinical manifestations, and this heterogeneity can partially be explained by differences in HLA-associations (HLA-Cw*0602 versus HLA-B*27, for example).
Moreover, the genotype of patients in the PsA cohort was shown to be heterogeneous with significant elevations in the frequency of haplotypes containing HLA-B*08, HLA-C*06:02, HLA-B*27, HLA-B*38 and HLA-B*39.
Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022).
Therefore these results suggest that the HLA-E and HLA-C(∗)02 molecules may also play an important role in determination immune response contributing to the PsA development.
The major genetic risk factor for PsA is an HLA-C allele, and in recent genome-wide association studies few other susceptibility loci have as yet been identified.In this issue, Murdaca et al.
This large case-control and family based association study shows that HLA-C*12/B*38, HLA-B*27 and HLA-C*06/B*57 are haplotypes (alleles) robustly associated with PsA.
Psoriatic arthritis (PsA) is described as a multifactorial autoimmune rheumatic disease although its development is surely linked to some specific HLA genes (especially the HLA-Cw*06:02 allele).
The MICA-129 methionine (Met) allele, particularly Met/Met homozygosity, was strongly associated with both cutaneous psoriasis (PsC) and psoriatic arthritis (PsA) independently of HLA-B and HLA-C in Toronto patients, and was also associated with PsA in St. John's patients, but with no additional effect of Met/Met homozygosity.
HLA-B*27, HLA-B*38 and HLA-C*06 frequencies were also significantly higher in patients with PsA than in healthy controls (B*27: OR 3.05, p<0.0001; B*38: OR 5.9, p<0.0001; HLA-C*06: OR 1.71, p<0.0001).
Similar to AS, the strongest genetic signal of susceptibility to psoriasis and psoriatic arthritis also emanates from the MHC region (attributable mostly to HLA-C(*)06:02 although other genes have been implicated), and gene-gene interaction of HLA-C with ERAP1.
Only three modestly sized genome-wide association studies of PsA have been undertaken to date, but they have identified the HLA-C region, IL12B, TRAF3IP2, and FBXL19 genes as being associated with PsA susceptibility.
Stratification by age of onset with 30 years as age limit is an effective means of identifying PSORS1-associated psoriasis in patients with psoriatic arthritis.
Other study findings, such as the relationship between HLA-C*06 and spondylitis or the protective effect of HLA-C*07 for the polyarthritis clinical phenotype of PsA, are of preliminary character and require verification.
Using a candidate gene approach, genes robustly confirmed to be associated with psoriasis vulgaris (PsV) have also been found to be associated with PsA (HLA-Cw*0602, IL23R, IL12B).
Four variants of the IL12B and IL23R genes were analyzed in 1,114 PV patients, 748 patients with psoriatic arthritis (PA) and 937 healthy controls before and after stratification for the major psoriasis risk allele at psoriasis susceptibility locus 1 (PSORS1).