Abstract
Lipid metabolism plays an important role in viral infections. We aimed to assess the causal effect of lipid-lowering drugs (HMGCR inhibitiors, PCSK9 inhibitiors, and NPC1L1 inhibitior) on COVID-19 outcomes using two-sample Mendelian randomization (MR) study. We used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including expression quantitative trait loci 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). Summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) were used to calculate the effect estimates. SMR analysis found that a higher expression of HMGCR was associated with a higher risk of COVID-19 hospitalization (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 1.06-1.81). 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). No consistent evidence from both analyses was found for other associations. This two-sample MR study suggested a potential causal relationship between HMGCR inhibition and the reduced risk of COVID-19 hospitalization. Start-up Fund for high-level talents of Fujian Medical University.
Highlights
To validate the observed association using the eQTLs as an instrument, we proposed an instrument by selecting single-nucleotide polymorphisms (SNPs) within 100 kb windows from target gene of each drug that was associated with low-density lipoprotein (LDL) cholesterol level at a genome-wide significance level (p
Consortium for drugs target gene HMG-CoA Reductase (HMGCR), Proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-Like 1 (NPC1L1), respectively, and the most significant cis-eQTL SNP was selected as a genetic instrument for the target gene of each drug (Table 1, Supplementary File 1-Table 2)
A total of 7, 12, and 3 SNPs within or nearby gene HMGCR, PCSK9, and NPC1L1 were selected from a genome-wide association study (GWAS) summary data of LDL cholesterol levels in the Global Lipids Genetics Consortium, respectively (Table 1, Supplementary File 1-Table 3)
Summary
Available studies have suggested an important role of lipid metabolism in viral infections, including in the pathogenesis of SARS-CoV-2 infection (Proto et al, 2021). The plausible mechanisms include the involvement of host lipids in the virus life cycle, the influence of cholesterol on the immune cell functions, interfering with the mevalonate pathway, and so on (Proto et al, 2021). Such evidence indicates the potential protective effect of lipid-lowering drugs against COVID-19. Lipid metabolism plays an important role in viral infections. We aimed to assess the causal effect of lipid-lowering drugs (HMGCR inhibitiors, PCSK9 inhibitiors and NPC1L1 inhibitior) on COVID-19 outcomes using 2-sample Mendelian
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