Although a psoriasis susceptibility gene(s) has not been yet identified, a number of candidate genes were studied, with evidence for a major locus located within the major histocompatibility complex (PSORS 1).
Moreover, we need to determine allele-specific effects of ERAP1 variants in the context of HLA-B*51 and HLA-Cw*6, which are associated with Behçet's disease and psoriasis, respectively.
I review two examples of such challenges: the cloning of GPR154 (GPRA) and AAA1 on chromosome 7p14 at a susceptibility locus for atopy and asthma, and the study of HLA-Cw6, CCHCR1 (HCR) and CDSN on chromosome 6p21 at PSORS1, the major susceptibility locus for psoriasis.
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.
After adjusting for significant HLA-B and HLA-C alleles in multivariate analyses, MICA*016 remained significantly associated with psoriasis [odds ratio (OR) = 5.5, P = 0.008].
Of note, these 'MHC-I-opathies' show a differential immunopathology, probably reflecting antigenic differences within target tissues: HLA-B(*)51 is linked to ocular and mucocutaneous disease but not gut involvement, and HLA-C(*)0602 is linked to type I psoriasis but not scalp or nail disease.
Our results suggest that the MICA 5.1 allele might be a genetic marker related to the early onset of psoriasis and play a secondary role to the HLA-Cw*0602 gene or an unknown causative gene closely linked to HLA-Cw*0602 in the genetic susceptibility to psoriasis.
Comparing PsA and psoriasis, the prevalence of HLA-B*27 and HLA-Cw*12 were more common in PsA patients, while the prevalence of HLA-DR*07 was higher in those with psoriasis (p < 0.05).
There are several susceptibility genes for psoriasis residing in chromosome 6p near the HLA-C locus, including the corneodesmosin (CDSN) gene, the octamer transcription factor-3 (POU5F1) gene, the major histocompatibility complex class I chain-related gene A (MICA), and the gene for tumour necrosis factor (TNF)-alpha.
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 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).
PSORS1C2 is a gene located between coiled-coil alpha-helical rod protein 1 (CCHCR1) and corneodesmosin (CDSN) within the psoriasis susceptibility locus 1 (PSORS1).
However, HLA-Cw*0602 was significantly increased in patients with early-onset psoriasis (73.8% vs. 17%, p<0.0001), whereas the allele 384 of the microsatellite C1_4_4, located 34 kb telomeric to HLA-C locus, was increased only in late-onset cases (49% vs. 21%, p=0.001).
This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility.
More importantly we find that rs9468925 in HLA-C/HLA-B is associated with both psoriasis and vitiligo, providing first important evidence that two major skin diseases share a common genetic locus in the MHC, and a basis for elucidating the molecular mechanism of skin disorders.
The low-expressing HLA-E*01:01 allele was associated with psoriasis (P = 0.0018), although this association was dependent on HLA-C. Our findings support a potential immunoregulatory role for NK cells in psoriasis and suggest the importance of future studies to investigate the contribution of NK cells and their regulatory receptors to the pathogenesis of psoriasis.
Moreover, genetic interaction between LCE3C_LCE3B-del and HLA-C*06, located in the psoriasis susceptibility regions 4 and 1 (PSORS4 and 1), has been reported in several populations.
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).
The method is applied to PSORS1, a locus within the major histocompatibility complex (MHC) for which linkage and linkage disequilibrium with psoriasis has already been demonstrated.