Human Genetics Unit, Biological Sciences Division, Indian Statistical Institute, Kolkata, India.
Department of Dermatology, Institute of Post Graduate Medical Education & Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, India.
J Invest Dermatol. 2021 Nov;141(11):2630-2638.e7. doi: 10.1016/j.jid.2021.04.020. Epub 2021 May 21.
Functional studies to delineate the molecular mechanisms of causal genetic variants are the main focus in the post-GWAS era. Previous GWASs have identified >50 susceptibility loci associated with psoriasis. Functional understanding of the biology underlying the disease risk of most of these associated loci is unclear. In this study, we identified a regulatory SNP at the putative enhancer of the LCE3A gene within the epidermal differentiation complex that showed epistatic interaction with HLA-Cw6. The variant allele disrupted signal transducer and activator of transcription 3 binding to the region, thereby regulating the expression of the downstream LCE3A gene. Electrophoretic mobility shift and pulldown assay confirmed the preferential binding of signal transducer and activator of transcription 3 to the DNA with a wild-type allele compared with the DNA with a variant allele. The reporter assay further validated the IL-6‒stimulated phosphorylated signal transducer and activator of transcription 3‒mediated LCE3A activation in the presence of the wild-type allele. Interestingly, the presence of the HLA-Cw6 allele leads to IL-6‒mediated phosphorylation of signal transducer and activator of transcription 3, followed by its nuclear localization in the epidermal keratinocytes of psoriatic skin, suggesting indirect interaction of the HLA-Cw6 allele and a regulatory SNP upstream of the LCE3A gene. This study reflects an interesting approach to dissecting the molecular mechanism underlying the genetic interaction observed between HLA-Cw6 and LCE3A in psoriasis pathogenesis.
在 GWAS 后时代，阐明因果遗传变异的分子机制的功能研究是主要焦点。先前的 GWAS 已经确定了 >50 个与银屑病相关的易感性位点。对于这些相关位点中大多数的疾病风险的生物学功能理解尚不清楚。在这项研究中，我们在表皮分化复合物内的 LCE3A 基因的假定增强子中鉴定了一个调节性 SNP，该 SNP 与 HLA-Cw6 表现出上位性相互作用。变异等位基因破坏了信号转导和转录激活因子 3 与该区域的结合，从而调节下游 LCE3A 基因的表达。电泳迁移率变动和拉下测定证实，与具有变异等位基因的 DNA 相比，信号转导和转录激活因子 3 优先结合具有野生型等位基因的 DNA。报告基因测定进一步验证了在存在野生型等位基因的情况下，IL-6 刺激的磷酸化信号转导和转录激活因子 3 介导的 LCE3A 激活。有趣的是，HLA-Cw6 等位基因的存在导致信号转导和转录激活因子 3 的 IL-6 介导的磷酸化，随后在银屑病皮肤的表皮角质形成细胞中发生其核定位，表明 HLA-Cw6 等位基因和 LCE3A 基因上游的调节性 SNP 之间的间接相互作用。这项研究反映了一种有趣的方法，可以剖析在银屑病发病机制中观察到的 HLA-Cw6 和 LCE3A 之间遗传相互作用的分子机制。
