Lipids, lipid-lowering drugs and the risk of herpes zoster: a Mendelian randomization study

Observational studies have shown that the risk of developing herpes zoster (HZ) increases with the use of statins. However, there are many confounding factors in observational studies. Therefore, our Mendelian randomization (MR) study aimed to explore the causal role of lipids in HZ and to assess the causal impact of lipid-lowering drug targets on HZ risk. Our study used low-density lipoprotein (LDL) as a biomarker, and MR analysis was applied to study the effects of genetic inhibition of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR, targeted by statins), Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by, e.g., alirocumab) on the risk of HZ. Second, we analyzed the overall effect of different lipid traits, including LDL, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs), on the HZ. Finally, we analyzed the causal association between cardiovascular disease (CVD) and HZ. The primary MR analysis employed the inverse variance weighted (IVW) approach, which MR supplemented‒Egger, weighted median and weighted mode methods. In addition, we performed sensitivity analysis to assess the robustness of the results and the presence of bias. Heterogeneity and pleiotropy analyses were performed to ensure the accuracy of the results. Genetically modified HMGCR inhibition was significantly associated with an increased risk of HZ (OR: 2.02, per standard deviation reduction in LDL; 95% CI 1.05-3.90; P = 0.035, P(BH) = 0.0525 < 0.1). Moreover, genetically proxied PCSK9 inhibition was associated with a reduced risk of HZ (OR: 0.58, per standard deviation reduction in LDL; 95% CI 0.42-0.80; P = 0.001, P(BH) = 0.003 < 0.1). Sensitivity analysis did not provide statistical evidence of bias from pleiotropy or genetic confounding. No robust association was found for NPC1L1 inhibition. No significant effect of lipid traits or CVD on HZ risk was found. Our findings did not support dyslipidemia and CVD as causal factors for HZ. Among the three lipid-lowering drug targets, HMGCR inhibition (targeted by statins) was associated with an increased risk of HZ, and PCSK9 is a promising candidate drug target in HZ. These findings have important implications for understanding the pathogenesis of HZ and for the development of new therapeutic strategies.