Yang Yang, Liu Dingxuan, Ai Zhen, Gao Xi
Heilongjiang University of Chinese Medicine, Heilongjiang, China.
First Hospital of Heilongjiang University of Chinese Medicine, Heilongjiang, China.
Medicine (Baltimore). 2025 Sep 12;104(37):e44382. doi: 10.1097/MD.0000000000044382.
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.
椎间盘退变（IVDD）是颈部、背部和下背部疼痛的常见原因，也是一个重大的全球公共卫生问题。乳酸是椎间盘细胞的代谢产物，与椎间盘退变密切相关。由乳酸驱动的乳酸化（Lac）与椎间盘退变有关，靶向相关基因可能为椎间盘退变提供新的治疗方向。在本研究中，将全基因组关联研究的数据与与Lac积累相关的药物以及与Lac相关的表达定量性状位点（eQTL）相结合，以探索Lac相关基因与椎间盘退变之间的关系。来自MSigDB的Lac相关基因、来自FinnGen的椎间盘退变全基因组关联研究数据以及来自eQTLGen联盟的顺式eQTL数据。主要采用逆方差加权（IVW）方法进行评估，并使用加权中位数、简单模式和加权模式进行敏感性分析，这些分析支持了与IVW方向一致的结果的稳健性。Cochran Q检验评估工具变量异质性（P>0.05），后验概率PP.H4>0.80被认为是共定位的有力证据。共有36个潜在基因在IVW方法中达到统计学显著性（P<0.05），但在所有敏感性分析方法中，有23个基因的效应方向与IVW相同，表明具有高度稳健性。贝叶斯共定位分析确定了NFU1（PP.H4 = 1.00，OR = 1.18 [1.13 - 1.24]）和NDUFA13（PP.H4 = 0.90，OR = 0.81 [0.74 - 0.89]），表明这两个基因共享与IVDD风险相关的因果变异。NFU1是IVDD的一个强风险因素，因此选择的主要药物类型是“抑制剂”。NDUFA13对IVDD有保护作用，因此选择的药物类型是“激动剂”。Lac与IVDD之间存在因果关联，通过调节Lac相关可药物化基因的表达可以延缓IVDD的进展。
