Psoriasis susceptibility locus 1 (PSORS1) was the first PS susceptibility locus to be localized and maps to the MHC class I region. The strong association between PSORS1 and HLA-Cw650,51–58
is estimated to account for one-third to one-half of the genetic liability to PS59
HLA-Cw*0602 is also increased among patients with PsA compared to controls48
() and leads to earlier mean age of onset of PS in PsA patients (p = 0.003).48
Genes/SNPs associated with PsA. Numbers of cases/controls used for each study along with corresponding odds ratios (ORs) and P values are shown.
GWAs studies also indicate that alleles from the HLA class I region are more highly associated with PsA than any other loci in the genome are60
. The SNPs most highly associated with PsA tag HLA-Cw*0602, but also the rarer and closely-related HLA-Cw*1203 allele.56,57
Interestingly, and as described elsewhere, HLA-Cw*0602 and HLA-Cw*1203 may recognize the same antigen since they are identical in their alpha-2 domains and peptide binding pockets C, D, and E.56
However, they differ by five amino acids in their alpha-1 domain, placing them in different killer cell immunoglobulin-like receptor (KIR) ligand groups. As other independent studies point to HLA-Cw*0602 alone as being the PSORS1 risk allele,52
functional studies may be needed to resolve this discrepancy and to conclusively rule out SNPs affecting expression of HLA-C alleles or other skin specific genes in this region such as corneodesmosin and alpha-helix coiled-coil rod homolog gene (HCR).53, 54, 58, 61–63
Earlier studies on PsA associations with MHC alleles were generally performed with small numbers of patients but deserve some discussion. HLA-B27 is associated with spinal involvement, whereas HLA-B38 and B39 are associated with peripheral polyarthritis.64
These latter two alleles are highly correlated with HLA-Cw*1203, hence, this earlier finding may be due to the HLA-Cw*1203 association with PsA. The presence of the RA “shared epitope” HLA-DRB1 from the HLA class II region is reported to be associated with radiological erosions in PsA.65
Moreover, HLA-B39 alone, HLA-B27 in the presence of HLA-DR7, and HLA-DQw3 in the absence of HLA-DR7, are reported to confer an increased risk for disease progression. Conversely, HLA-B22 is reported to be protective for disease progression.64
Patients with both HLA-Cw6 and HLA-DRB1*07 alleles are reported to have a less severe course of arthritis than patients with HLA-C26 or HLA-DRB1*07 alone.66
It is not clear if some of these associations are due to “linkage disequilibrium” within the MHC, reflecting a predisposing haplotype harboring a different risk factor, or are truly causative themselves.
Tumor necrosis factor alpha (TNFA
) polymorphisms are of interest given the success of anti-TNF agents in PS and PsA. The polymorphisms that are associated with PS and PsA, such as those in the TNFA
promoter at positions −238 and −308, have been demonstrated to be due to linkage disequilibrium with HLA-Cw*0602.67
However, TNF*-857T, may represent a risk factor for PsA that is independent of the PSORS1 allele.67
In the case of PsA susceptibility, there are also important interactions with certain HLA-class I alleles and killer inhibitory receptors (KIRs) that are located on chromosome 19. Susceptibility to PsA is strongly associated with the presence of KIR2DS1 and/or KIR2DS2 plus HLA-Cw ligand group homozygosity (so that an inhibitory signal is diminished).68,69,70
Certain combinations of natural killer receptors and HLA-B alleles are also associated with slower time to develop AIDS, and lower risk of HIV infection in exposed uninfected individuals71
. These include the combined genotype of KIR3DL1
high expressing alleles and HLA-B*57 which is associated with PsA. Certain combinations of HLA and KIR are also reported to affect outcome to infection by other viruses such as hepatitis B virus, hepatitis C virus and human papilloma virus72
. It is tempting to speculate that selection of alleles in the past that protected against viral infection lead to susceptibility to diseases such as psoriatic arthritis.