Risk SNP-mediated enhancer-promoter interaction drives keloid through lncRNA DEIK

Genetics is a major factor for keloid predisposition and the genome-wide association study (GWAS) has identified a single nucleotide polymorphism (SNP) rs873549 at 1q41 as a susceptibility locus. However, the functional significance of this locus in keloid pathogenesis remains elusive. Here, we found that rs1348270, an enhancer located SNP in strong linkage disequilibrium with rs873549, mediated looping with the promoter of a lncRNA DEIK (Down Expressed In Keloids, formerly RP11-400N13.1). The risk variant was associated with decreased enhancer-promoter interaction and DEIK expression. Mechanistically, downregulation of DEIK increased the expression of collagens and chondrocyte and osteocyte associated genes such as POSTN and COMP through upregulating BMP2. Furthermore, correlation analysis revealed that DEIK expression was inversely correlated with BMP2, POSTN and COMP expression in keloid and normal fibroblasts. These findings uncover new mechanisms underlying genetic factor-mediated keloid predisposition and identify potential targets for keloid therapies. Overall design: Comparative gene expression profiling analysis of RNA-seq data for fibroblasts and its knockdown derivatives (siDEIK).