School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China.
Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5, Beixian Pavilion, Xicheng District, Beijing, 100053, China.
Lipids Health Dis. 2024 Oct 2;23(1):327. doi: 10.1186/s12944-024-02311-w.
Abnormal lipid metabolism is linked to intervertebral disc degeneration (IVDD), sciatica, and low back pain (LBP), but it remains unclear whether targeted interventions can prevent these issues. This study investigated the causal effects of lipid-lowering drug use on IVDD, sciatica, and LBP development.
Single-nucleotide polymorphisms (SNPs) linked to total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and non-high-density-lipoprotein cholesterol (non-HDL-C) were obtained from the Global Lipids Genetics Consortium's genome-wide association study (GWAS). Genes near HMGCR, PCSK9, and NPC1L1 were selected to represent therapeutic inhibition targets. Using Mendelian randomization (MR) focusing on these drug targets, we identified causal effects of PCSK9, HMGCR, and NPC1L1 on the risk of developing IVDD, sciatica, and LBP, with coronary heart disease risk serving as a positive control. Using summary data from Mendelian randomization (SMR) analysis, we evaluated potential therapeutic targets for IVDD, sciatica, and LBP through protein quantitative trait loci (pQTL). The genetic associations with IVDD, sciatica, LBP, and coronary heart disease were derived from FinnGen (discovery) and UK Biobank (replication). Additionally, a cross-sectional observational study was performed using data from the National Health and Nutrition Examination Survey (NHANES) to further investigate the connection between LBP and statin use, with a sample size of 4343 participants. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to assess the outcomes.
The NHANES-based cross-sectional study indicated that non-statin use was associated with an increased risk of developing LBP (OR = 1.29, 95% CI [1.04, 1.59], P = 0.019). Moreover, Inverse-variance weighting (IVW) analysis revealed that NPC1L1-mediated reductions in TC, LDL-C, and non-HDL-C concentrations were associated with a decreased risk of developing IVDD (P = 9.956E-03; P = 3.516E-02; P = 1.253E-04). Similarly, PCSK9-mediated reductions in LDL-C and TC concentrations were linked to a lower risk of developing sciatica (P = 3.825E-02; P = 2.709E-02). Sensitivity analysis confirmed the stability and reliability of the MR results. MST1 (macrophage stimulating 1) levels was inversely associated with IVDD, sciatica, and LBP risks.
The results of cross-sectional study suggested that non-use of statins was positively correlated with LBP. The results of Mendelian randomization study suggest that NPC1L1 could lower the risk of developing IVDD by reducing TC, LDL-C, and non-HDL-C levels. Additionally, PCSK9 may reduce the risk of developing sciatica by lowering LDL-C and TC levels. In contrast, HMGCR appears to have no significant effect on IVDD, sciatica, or LBP development. Nonetheless, further research is needed to verify these preliminary results. MST1 warrants further exploration as a potential therapeutic target. It is necessary to do further research to validate these findings.
异常的脂质代谢与椎间盘退行性变（IVDD）、坐骨神经痛和下腰痛（LBP）有关，但尚不清楚靶向干预是否可以预防这些问题。本研究调查了降脂药物使用与 IVDD、坐骨神经痛和 LBP 发展之间的因果关系。
从全球脂质遗传学联合会的全基因组关联研究（GWAS）中获得与总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）和非高密度脂蛋白胆固醇（非 HDL-C）相关的单核苷酸多态性（SNP）。选择靠近 HMGCR、PCSK9 和 NPC1L1 的基因来代表治疗抑制靶点。使用针对这些药物靶点的孟德尔随机化（MR），我们确定了 PCSK9、HMGCR 和 NPC1L1 对 IVDD、坐骨神经痛和 LBP 发病风险的因果影响，以冠心病风险作为阳性对照。使用孟德尔随机化（SMR）分析的汇总数据，我们通过蛋白质数量性状基因座（pQTL）评估了 IVDD、坐骨神经痛和 LBP 的潜在治疗靶点。从 FinnGen（发现）和 UK Biobank（复制）中得出与 IVDD、坐骨神经痛、LBP 和冠心病相关的遗传关联。此外，使用来自国家健康和营养检查调查（NHANES）的数据进行了一项横断面观察性研究，以进一步研究 LBP 与他汀类药物使用之间的关系，样本量为 4343 名参与者。计算了比值比（OR）和相应的 95%置信区间（CI）来评估结果。
基于 NHANES 的横断面研究表明，非他汀类药物的使用与 LBP 发病风险增加有关（OR=1.29，95%CI[1.04，1.59]，P=0.019）。此外，逆方差加权（IVW）分析表明，NPC1L1 介导的 TC、LDL-C 和非 HDL-C 浓度降低与 IVDD 发病风险降低相关（P=9.956E-03；P=3.516E-02；P=1.253E-04）。同样，PCSK9 介导的 LDL-C 和 TC 浓度降低与坐骨神经痛发病风险降低相关（P=3.825E-02；P=2.709E-02）。敏感性分析证实了 MR 结果的稳定性和可靠性。MST1（巨噬细胞刺激 1）水平与 IVDD、坐骨神经痛和 LBP 风险呈负相关。
横断面研究的结果表明，他汀类药物的非使用与 LBP 呈正相关。孟德尔随机研究的结果表明，NPC1L1 通过降低 TC、LDL-C 和非 HDL-C 水平可能降低 IVDD 的发病风险。此外，PCSK9 可能通过降低 LDL-C 和 TC 水平降低坐骨神经痛的发病风险。相比之下，HMGCR 似乎对 IVDD、坐骨神经痛或 LBP 发病没有显著影响。然而，需要进一步的研究来验证这些初步结果。MST1 作为一种潜在的治疗靶点值得进一步探索。有必要进行进一步的研究来验证这些发现。
