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Potential extracellular matrix-associated pathogenic genes in skin fibrosis: A multi-omics Mendelian randomization
Teng Gong1, Zhaorong Xu1, Minjuan Wu2
1Burn & Wound Repair Department, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Fujian Burn Institute, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Fujian Burn Medical Center, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China; Fujian Provincial Key Laboratory of Burn and Trauma, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China.
Background:
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.
Aims:
The study aimed to identify potential causal links between ECM-related genes and the risk of developing skin fibrosis.
Methods:
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.
Results:
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.
Conclusions:
Our findings nominate HSF1 as a potential novel risk factor for skin fibrosis, underscoring the need for further research into its underlying mechanisms.
