## 6 Psoriasis  
PV is a common and chronic inflammatory disease, which can affect the skin, nails and joints. It is characterised by immune-mediated epidermal hyperproliferation [86]. It is a highly heritable disease, with increased concordance in monozygotic _versus_ digygotic twins (65%-72% _versus_ 15%-30% respectively) [87]. During the last 10 years, almost 40 GWAS-identified novel psoriasis-susceptibility loci have been identified and more recently, the genes within these loci and their significance to the pathophysiology of PV are becoming clearer [88]. Interestingly, several show clustering to a distinct segment of the inflammatory cascade [89]. Psoriasis susceptibility locus 1 (_PSORS1_), located on the MHC region on chromosome 6p21, has been most consistently identified in GWAS with a significant odds ratio of 3.0 [90]. Genes implicated within this 250 kb interval include _HLA-C_ (human leukocyte antigen C), _CCHCR1_ (coiled-coil \(\alpha\)-helical rod protein 1), and _CDSN_ (corneodesmosin). These were considered as potential disease-associated genes due to their function and the presence of disease-associated SNPs within their coding sequence [91]. Identification of the causal disease susceptibility allele was extremely challenging, ultimately [PERSON] _et al._ (2006) sequenced the entire _PSORS1_ region in individuals bearing different _HLA-C_ alleles to identify SNPs unique to the _PSORS1_ haplotype. They indicated that _HLA-Cw6_ was the major _PSORS1_ disease allele [92], reflecting the importance of antigen presentation in the pathophysiology of PV. Identification of susceptibility loci has contributed to our understanding of PV pathogenesis, which appears to involve the innate and adaptive immune responses. Pathways that have been identified in various studies include IL12/IL17 axis activation (_IL23R_, _IL12B_, _IL23A_, and _TRAF31P2_), type 1 interferon induction (_IFIH1_, _RNF114_, and _TYK2_) and NF-kB signaling (_CARD14_, _REL_, _NFKBIA_, _TNFAIP3_, and _TNF1P_) [90, 92, 93, 94, 95, 96, 97]. Of particular interest is the Th1-Th17 axis, involving the recently described subset of IL17 expressing T cells (Th17) [98] which is thought to play a major role in the development and maintenance of psoriatic plaques [97]. IL12 and IL23 are cytokines that induce naive CD4\({}^{+}\) lymphocytes to differentiate into type 1 helper cells and type 17 helper cells, both of which are key mediators of PV [97]. IL12 and IL23 share a common p40 subunit encoded by the _IL12B_ gene. In mice, injection of IL23 results in epidermal hyperplasia, which is mediated by IL22 produced by Th17 cells. This shows similarities to phenomena observed in humans [99]. GWAS have identified three SNPs with strong evidence of association with PV mapping near _IL12B_, _IL23A_ (encoding the p19 subunit of IL23) and _IL23R_ (encoding a subunit of the IL23 receptor) [94] raising the possibility that dysregulated IL23 signaling could lead to chronic immune responses within epithelial cells. Ustekinumab (Stelara(r)) is a human IgG1k monoclonal antibody against the p40 subunit of the IL12 and IL23 cytokines that has demonstrated significant improvement in outcome measures for the treatment of PV in Phase III clinical trials [100]. A significant proportion of patients had at least 90% improvement in their psoriasis area-and-severity index (PASI) score, with a proportion experiencing complete clearance by 12 weeks [100]. These findings also establish a central role for the IL12/IL23 p40 cytokines in the pathophysiology of PV. Another approach to utilise the discoveries gained from GWAS studies is personalised medicine. For example, patients with PV who carry risk variants in _IL12B_ may benefit preferably from a monoclonal antibody targeting its p40 subunit, e.g., Ustekinumab. Studies using molecular profiling of PV and clinical phenotyping to predict treatment response have shown promise [101] and larger studies are underway.