Association of lipid-lowering drugs with COVID-19 outcomes: A Mendelian Randomization study

Huang, W.; Xiao, J.; Ji, J.; Chen, L.-W.

Background: Lipid metabolism plays an important role in viral infections. Large cohort study suggested a protective potential of lipid-lowering drugs in COVID-19 outcomes, but the nature of observational study precludes it to draw a causal inference. Objectives: To assess the causal effect of lipid-lowering drugs (HMGCR inhibitors, PCSK9 inhibitors and NPC1L1 inhibitors) on COVID-19 outcomes using 2-sample Mendelian Randomization (MR) study. Methods: We used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including expression quantitative trait loci (eQTLs) of drugs target genes, and genetic variants within or nearby drugs target genes associated with low-density lipoprotein (LDL) cholesterol from genome-wide association study (GWAS). GWASs of COVID-19 outcomes (susceptibility, hospitalization and very severe disease) were obtained from the COVID-19 Host Genetics Initiative. Summary-data-based MR (SMR) and inverse-variance weighted MR (IVW-MR) were used to calculate the effect estimates. Results: SMR analysis found that a higher expression of HMGCR was associated with a higher risk of COVID-19 hospitalization (OR=1.38, 95%CI=1.06-1.81; P=0.019). Similarly, IVW-MR analysis observed a positive association between HMGCR-mediated LDL cholesterol and COVID-19 hospitalization (OR=1.32, 95%CI=1.00-1.74; P=0.049). No consistent evidence from both SMR and IVW-MR analyses was found for the association of HMGCR inhibitors with COVID-19 susceptibility or very severe disease, or for the association of PCSK9 inhibitors and NPC1L1 inhibitor with COVID-19 outcomes. Conclusions: In this 2-sample MR study, we found potential causal evidence that HMGCR inhibitors could reduce the risk of COVID-19 hospitalization. Further research is needed to explore the therapeutic role of statins for COVID-19.