Association between lipid-lowering agents with intervertebral disc degeneration, sciatica and low back pain: A drug-targeted Mendelian randomized study and cross-sectional observation

Background : Abnormal lipid metabolism is linked to intervertebral disc degeneration (IVDD), sciatica, and low back pain (LBP), but it remains unclear whethertargeted interventions can prevent these issues. This study investigated the causal effectsof lipid-lowering drug use on IVDD, sciatica, and LBP development. Methods : 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) studies 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. 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. Results : 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 revealedthat 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). However, the colocalization analysis did not reveal any significant associations. Sensitivity analysis confirmed the stability and reliability of the MR results. Conclusion : 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.