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.
The S gene (corneodesmosin), located 160 kb telomeric of HLA-C, is a strong candidate for psoriasis due to its reportedly exclusive expression in differentiating keratinocytes.
Strong additive effects when combining HLA-C*06 with IL23A, IL23R, IL12B, NFKB1 or TNIP1 were restricted to the severe cohort, indicating that activation of these pathways may influence disease severity in psoriasis.
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 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.
Recent work has suggested that HLA-Cw6 on chromosome 6 is the risk variant in the PSORS1 [MIM 177900] susceptibility locus that confers the greatest risk for early onset of psoriasis.