Potential extracellular matrix-associated pathogenic genes in skin fibrosis: A multi-omics Mendelian randomization study.

Abstract

Skin fibrosis is a condition whose underlying genetic mechanisms are largely unexplored. Understanding the genetic factors linked to the extracellular matrix (ECM) could provide insights into its progression. The study aimed to identify potential causal links between ECM-related genes and the risk of developing skin fibrosis. Researchers collected ECM-related genes from GeneCards and integrated quantitative trait loci (QTL) data-specifically gene expression (eQTLs), DNA methylation (mQTLs), and protein expression (pQTLs). The discovery cohort utilized genome-wide association study (GWAS) data from the FinnGen database and was verified using data from the UK Biobank and GWAS Catalog. Summary data-based Mendelian randomization (SMR) analysis was performed, complemented by colocalization analysis. The SMR analysis identified 329 mQTLs, 15 eQTLs, and 11 pQTLs in the discovery cohort, with colocalization confirming 228 mQTLs, 9 eQTLs, and 9 pQTLs. Notably, hypomethylation of the HSF1 gene (cg18814314) may upregulate its expression and protein levels, which could increase the risk of skin fibrosis. Our findings nominate HSF1 as a potential novel risk factor for skin fibrosis, underscoring the need for further research into its underlying mechanisms.