Role of interleukin 6 signaling pathway in the anti-inflammatory effects of statins on coronary artery disease: Evidence from Mendelian randomization analysis

Abstract

BackgroundStatins are currently widely used in the prevention of coronary artery disease (CAD) primarily for lipid-lowering with a potential anti-inflammatory effect. However, it is not clear if their potential anti-inflammatory effects are mediated through the interleukin 6 (IL-6) signaling pathway. MethodsUsing the Mendelian randomization (MR) approach followed by multivariable MR analyses, we examined the extent to which the effects of statins on CAD might be mediated through the IL-6 signaling pathway. ResultsOur observations showed that HMG-CoA reductase, using LDL levels as a proxy, had a significant effect on upstream IL-6 (βMR = 0.47, P-IVW = 0.01) and nominally significant effects on IL-6RA (βMR = 0.22, P-IVW = 0.047) and APOB (βMR = 0.82, P-IVW = 1.8 × 10–33). While the IL-6 signaling cascade (IL-6RA βMR = −0.06, P-IVW = 3.45 × 10–20 and IL-6 βMR = −0.03, P-IVW = 0.09) and the anti-inflammatory effect of HMG-CoA reductase (βMR = −0.31, P-IVW = 0.01) was found to influence the risk of CAD, the multivariable MR (MVMR) model indicated that the anti-inflammatory effect of HMG-CoA reductase is not likely to be mediated through the IL-6 signaling cascade, including APOB and IL-6RA (MVMRβ = 0.23, P = 0.688). ConclusionsOur findings suggest that statins may use inflammatory mechanisms independent of the IL-6 signaling pathway to prevent CAD. This result could potentially affect the definition of the target population for statin use.