Lumbar disc herniation (LDH) is a prevalent spinal disorder. Although empirical investigations have indicated correlations between circulating proteins/metabolites and LDH, their causal roles remain unclear. To elucidate these potential causal relationships, we employed Mendelian randomization (MR) methodology. Specifically, we conducted a comprehensive two-sample MR study to assess the causality of 4,907 circulating proteins and 1,400 plasma metabolites on LDH risk within a European-ancestry population. We validated significant associations using sensitivity analyses (weighted median, MR-Egger, MR-PRESSO) and consolidated primary findings via comprehensive analysis with multiple-testing-corrected thresholds. Then, reverse MR analysis was used to test for bidirectional causal relationships between LDH and the identified proteins. This was followed by the construction of a protein-protein interaction network and enrichment analysis, aimed at deciphering the biological relevance of these proteins to LDH. Genetic instruments for the circulating proteins were derived from a large-scale pQTL (protein quantitative trait loci) investigation involving 35,559 individuals, which provided data on 4,907 proteins. Data for plasma metabolites were obtained from a relevant GWAS of 14,296 subjects. Meanwhile, summary statistics for LDH were sourced from the large-scale FinnGen R12 database. Our analysis identified 44 plasma proteins and 23 plasma metabolites with putative causal effects on LDH. For the most significant results derived from the two sets of MR analyses, the inverse-variance weighted method was applied, followed by a meta-analysis. Subsequent pathway analysis delineated four key metabolic pathways, unveiling promising therapeutic targets for LDH intervention (ENPP2, FTMT, PAPOLG).

Linhan Qin, Qinghua Ding. Dissecting Causal Relationships between Metabonomics, Circulating Plasma Proteomics, and Lumbar Disc Herniation: A Mendelian Randomization Study. Frontiers in Medical Science Research (2025), Vol. 7, Issue 6: 125-140. https://doi.org/10.25236/FMSR.2025.070616.

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