Inhibition of lactylation by LRP1 expression increases the risk of intervertebral disc degeneration: A multi-omics summary-based Mendelian randomization analysis

Intervertebral disc degeneration (IVDD) causes neck, back and low back pain, and is a major global public health problem. Lactate, a metabolic product of disc cells, relates closely to degeneration. Lactylation, driven by lactic acid, associates with IVDD; targeting related genes may offer new therapies. This study aimed to identify causal lactylation-related genes in IVDD via multi-omics summary-based Mendelian randomization (SMR). In this study, data from a genome-wide association study (GWAS) were combined with methylation quantitative trait loci (mQTL) and expression quantitative trait loci (eQTL) to investigate the relationship between lactylation-related genes and disc degeneration. Lactylation-related genes from GeneCards, IVDD GWAS data from FinnGen, cis-eQTL data from eQTLGen Consortium, cis-mQTL data from SMR. SMR analysis and HEIDI tests were used to assess causality, and associations within mQTL-eQTL pathways were analyzed using multicohort data. Significance of results was determined using p_SMR < .05 and p_HEIDI > .01. At the gene expression level, 11 lactylation-related genes were identified, of which KAT5, CEACAM6, NR6A1, MRE11, LUC7L2, H2BC12, and RARG were negatively correlated with the risk of IVDD, and H4C8, SIRT1, H2AC6, and LRP1 were positively correlated with the risk of IVDD. At the DNA methylation level, 27 CpG sites near 14 genes were found to have a causal effect on IVDD, however, when combined with the causal effect of gene expression, only 11 CpG sites near 4 genes existed that had a causal effect. After integrating the multi-omics data between mQTL and eQTL, we identified 3 lactylation-related genes, KAT5, CEACAM6, and LRP1. cg01515074 methylation-induced upregulation of LRP1 increases degeneration risk, while cg12146864 methylation-mediated downregulation of LRP1 reduces this risk, collectively reinforcing the role of LRP1 as a key driver in IVDD pathogenesis. In this study, we identified lactylation-related genes that have a causal role in IVDD, mainly LRP1. The resulting study emphasizes the importance of LRP1 in the pathogenesis of IVDD, with the potential to be a therapeutic target. Integration of multi-omics data has provided new understanding in the molecular mechanisms of IVDD pathogenesis and new strategies for targeted therapy.