Skin eQTL-Cerebrospinal Fluid Metabolites-Keloid Axis: An Integrative Multi-Omics Mediation Mendelian Randomization...

Area of Science:

• Genetics and Molecular Biology
• Dermatology
• Metabolomics

Background:

• Keloids are complex fibroproliferative disorders with poorly understood genetic underpinnings.
• Excessive extracellular matrix deposition and recurrence are hallmarks of keloids.
• The interplay between genetic variations, molecular phenotypes, and keloid susceptibility requires elucidation.

Purpose of the Study:

• To identify causal pathways linking skin gene expression, cerebrospinal fluid (CSF) metabolites, and keloid susceptibility.
• To investigate the roles of specific genes and metabolites in keloid pathogenesis.
• To nominate potential therapeutic targets for keloid prevention and treatment.

Main Methods:

• Integrated GTEx skin expression quantitative trait loci (eQTL) data with GWAS statistics for 338 CSF metabolites.
• Employed a three-step Mendelian randomization (MR) framework using two independent European keloid GWAS datasets.
• Validated findings using bulk and single-cell RNA-sequencing, and in vitro cell experiments.

Main Results:

• Four CSF metabolites (sphingomyelin, SOPC, N-acetylarginine, X-23593) were causally associated with increased keloid risk.
• PARP14 was identified as an upstream risk gene, while ALDH2 emerged as a protective gene mediated by SOPC.
• Elevated PARP14 and reduced ALDH2 expression were localized to specific cell types involved in pro-fibrotic signaling.

Conclusions:

• A novel skin eQTL → CSF metabolite → cell-state axis in keloid pathogenesis was delineated.
• PARP14, ALDH2, and SOPC-linked lipid remodeling are implicated as key mechanisms in keloid formation.
• These findings nominate specific molecular players for further mechanistic study and potential therapeutic targeting in keloids.