Functional Mapping of Genetic Interactions between HLA-Cw6 and LCE3A in Psoriasis

Functional studies to delineate the molecular mechanisms of causal genetic variants are the main focus in the post-GWAS era. Previous GWASs have identified more than 50 susceptibility loci associated with psoriasis. Functional understanding of the biology underlying the disease risk of most of these associated loci are unclear. Here, we identified a regulatory SNP at the putative enhancer of Late cornified envelope (LCE)-3A gene within the epidermal differentiation complex that showed epistatic interaction with the HLA-Cw6. The variant allele disrupted STAT3 binding to the region, thereby regulating the expression of the downstream LCE3A gene. Electrophoretic Mobility Shift and pull-down assay confirmed the preferential binding of STAT3 to the DNA with wild-type allele compared to variant allele. The reporter assay further validated the IL6 stimulated phospo-STAT3 mediated LCE3A activation in presence of the wild-type allele. Interestingly, the presence of HLA-Cw6 allele leads to IL6 mediated phosphorylation of STAT3 followed by its nuclear localisation in the epidermal keratinocytes of psoriatic skin, suggesting indirect interaction of HLA-Cw6 allele and regulatory SNP at the upstream of LCE3A gene. Our study reflects an interesting approach of dissecting the molecular mechanism underlying the genetic interaction observed between HLA-Cw6 and LCE3A in psoriasis pathogenesis.