Uncovering potential drug targets for lactylation-related genes mediated intervertebral disc degeneration: A Mendelian randomization analysis integrating eQTL data

Intervertebral disc degeneration (IVDD) is a common cause of neck, back, and low back pain, it is also a major global public health problem. Lactate is a metabolic product of intervertebral disc cells and is closely related to disc degeneration. Lactylation (Lac), driven by lactic acid, is associated with intervertebral disc degeneration, and targeting-related genes may provide new therapeutic directions for intervertebral disc degeneration. In this study, data from genome-wide association studies were combined with drugs associated with Lac accumulation and expression quantitative trait loci (eQTLs) associated with Lac to explore the relationship between Lac-related genes and disc degeneration. Lac-related genes from MSigDB, intervertebral disc degeneration genome-wide association studies data from FinnGen, and Cis-eQTL data from the eQTLGen consortium. The inverse variance weighting (IVW) method was primarily used for evaluation, and sensitivity analyses were conducted using weighted median, simple mode, and weighted mode, which supported the robustness of results consistent with the IVW direction. The Cochran Q test assessed instrumental variable heterogeneity (P > .05), and a posterior probability PP.H4 > 0.80 was considered strong evidence of co-localization. A total of 36 potential genes reached statistical significance (P < .05) in the IVW method, but 23 genes in all sensitivity analysis methods had the same effect direction as IVW, demonstrating high robustness. Bayesian co-localization analysis identified NFU1 (PP.H4 = 1.00, OR = 1.18 [1.13-1.24]) and NDUFA13 (PP.H4 = 0.90, OR = 0.81 [0.74-0.89]), indicating that these 2 genes share causal variants associated with the risk of IVDD. NFU1 is a strong risk factor for IVDD, so the main type of drug selected is an "inhibitor." NDUFA13 has a protective effect against IVDD, so the type of drug selected is an "agonist." There is a causal association between Lac and IVDD, and IVDD progression can be delayed by regulating the expression of Lac-related druggable genes.