Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study.
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ABSTRACT: Background
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.Methods
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.Results
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.Conclusions
This two-sample MR study suggested a potential causal relationship between HMGCR inhibition and the reduced risk of COVID-19 hospitalization.Funding
Start-up Fund for high-level talents of Fujian Medical University.
SUBMITTER: Huang W
PROVIDER: S-EPMC8709572 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRecent studies have highlighted the possible risk of neuropsychiatric adverse effects during treatment with lipid-lowering medications. However, there are still controversies that require a novel genetic-based approach to verify whether the impact of lipid-lowering drug treatment results in neuropsychiatric troubles including insomnia, depression, and neuroticism. Thus, we applied Mendelian randomization to assess any potential neuropsychiatric adverse effects of conventional lipid-lowering drugs such as statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and ezetimibe.MethodsA 2-sample Mendelian randomization study was conducted based on summary statistics from genome-wide association studies for lipids, insomnia, depression, and neuroticism. Single-nucleotide polymorphisms located in or near drug target genes of HMGCR, PCSK9, and NPC1L1 were used as proxies for statins, PCSK9 inhibitors, and ezetimibe therapy, respectively. To assess the validity of the genetic risk score, their associations with coronary artery disease were used as a positive control.ResultsThe Mendelian randomization analysis showed a statistically significant (P <.004) increased risk of depression after correcting for multiple testing with both statins (odds ratio=1.15, 95% CI: 1.04-1.19) and PCSK9 inhibitor treatment (odds ratio =1.19, 95%CI: 1.1-1.29). The risk of neuroticism was slightly reduced with statin therapy (odds ratio=0.9, 95%CI: 0.83-0.97). No significant adverse effects were associated with ezetimibe treatment. As expected, the 3 medications significantly reduced the risk of coronary artery disease.ConclusionUsing a genetic-based approach, this study showed an increased risk of depression during statin and PCSK9 inhibitor therapy while their association with insomnia risk was not significant.
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Project description:Background and aimsCholelithiasis etiology intricately involves lipid metabolism. We sought to investigate the plausible causal link between genetically proxied lipid-lowering medications-specifically HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors-and cholelithiasis risk.MethodsOur study utilized two genetic instruments for exposure to lipid-lowering drugs. These instruments encompassed genetic variants linked to low-density lipoprotein (LDL) cholesterol within or in proximity to drug target genes, along with loci governing gene expression traits of these targets. Effect estimates were derived through Inverse-variance-weighted MR (IVW-MR) and summary-data-based MR (SMR) methods.ResultsHigher HMGCR-mediated LDL cholesterol levels (IVW-MR, OR = 2.15, 95% CI = 1.58-2.94; P = 0.000) and increased HMGCR expression (SMR, OR = 1.19, 95% CI = 1.04-1.37; P = 0.014) are linked to elevated cholelithiasis risk, suggesting potential benefits of HMGCR inhibition. In contrast, higher PCSK9-mediated LDL cholesterol levels (IVW-MR, OR = 0.72, 95% CI = 0.56-0.94; P = 0.015) and increased PCSK9 expression (SMR, OR = 0.90, 95% CI = 0.82-0.99; P = 0.035) both correlate with lower cholelithiasis risk, indicating that PCSK9 inhibition may elevate this risk. Nevertheless, no substantial link emerged between NPC1L1-mediated LDL cholesterol or NPC1L1 expression and cholelithiasis in both IVW-MR and SMR analyses.ConclusionThis MR investigation affirms the causal link between the utilization of HMGCR inhibitors and a diminished risk of cholelithiasis. Additionally, it indicates a causal link between PCSK9 inhibitors use and increased cholelithiasis risk. However, no significant correlation was found between NPC1L1 inhibitors use and cholelithiasis risk.
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Project description:BackgroundStroke is a leading cause of death worldwide, but it is unclear whether circulating lipids and lipid-lowering drugs are causally associated with stroke and its subtypes.MethodsWe used two-sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid-lowering drugs on stroke and its subtypes.ResultsThe inverse variance weighted Mendelian randomization (IVW-MR) revealed the low-density lipoprotein cholesterol (LDL-C) (OR, 1.46; 95% CI, 1.17-1.83; p = 0.0008) and apolipoprotein B (apoB) (OR, 1.46; 95% CI, 1.21-1.77; p = 0.0001) was positively correlated with large artery stroke (LAS). However, no causal effect was found in LDL-C and apoB on LAS risk when we conducted mvMR. The IVW-MR also found a suggestive evidence that decreased LDL-C levels mediated by the PCSK9 (proprotein convertase subtilisin-kexin type 9) gene were associated with a reduced risk of any stroke (AS) (OR, 1.31; 95% CI, 1.13-1.52; p = 0.0003), any ischemic stroke (AIS) (OR, 1.29; 95% CI, 1.10-1.51; p = 0.001), and LAS (OR, 1.73; 95% CI, 1.15-2.59; p = 0.008), while NPC1L1 (Niemann-Pick C1-like protein)-mediated LDL-C levels were associated with a higher risk of small vessel stroke (SVS) (OR, 6.10; 95% CI, 2.13-17.43; p = 0.0008). The SMR revealed that expression of PCSK9 was associated with risk of AS (OR, 1.15; 95% CI, 1.03-1.28; p = 0.01), AIS (OR, 1.02; 95% CI, 1.14-1.29; p = 0.03), cardioembolic stroke (CES) (OR, 1.28; 95% CI, 1.01-1.61; p = 0.04). And, a significant association was found between the expression of NPC1L1 and the risk of SVS (OR, 1.15; 95% CI, 1.00-1.32; p = 0.04).ConclusionWe cautiously find that LDL-C and apoB was positively correlated with LAS. These findings suggest that the reducing LDL-C levels could be an effective prevention strategy for reducing the risk of stroke.
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Project description: Not available
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Project description:Accumulating observational studies suggested that hypercholesterolemia is associated with vascular dementia (VaD); however, the causality between them remains unclear. Hence, the aim of this study is to infer causal associations of circulating lipid-related traits [including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (apoA-I), and apolipoprotein B (apoB)] with VaD jointly using univariable MR (uvMR), multivariable MR (mvMR) and bidirectional two-sample MR methods. Then, the summary-data-based MR (SMR) and two-sample MR analysis were conducted to investigate the association of lipid-lowering drugs target genes expression (including HMGCR, PCSK9, NPC1L1, and APOB) and LDL-C level mediated by these target genes with VaD. The results of forward MR analyses found that genetically predicted HDL-C, LDL-C, TG, apoA-I, and apoB concentrations were not significantly associated with the risk of VaD (all p > 0.05). Notably, there was suggestive evidence for a causal effect of genetically predicted VaD on HDL-C via reverse MR analysis [odds ratio (OR), 0.997; 95% confidence interval (CI), 0.994−0.999; p = 0.022]. On the contrary, the MR results showed no significant relationship between VaD with LDL-C, TG, apoA-I, and apoB. The results for the SMR method found that there was no evidence of association for expression of HMGCR, PCSK9, NPC1L1, and APOB gene with risk of VaD. Furthermore, the result of MR analysis provided evidence for the decreased LDL-C level mediated by gene HMGCR reduced the risk of VaD (OR, 18.381; 95% CI, 2.092−161.474; p = 0.009). Oppositely, none of the IVW methods indicated any causal effects for the other three genes. Using genetic data, this study provides evidence that the VaD risk may cause a reduction of HDL-C level. Additionally, the finding supports the hypothesis that lowering LDL-C levels using statins may be an effective prevention strategy for VaD risk, which requires clinical trials to confirm this result in the future.
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Project description:ObjectiveTo examine whether genetic variation affecting the expression or function of lipid-lowering drug targets is associated with Alzheimer disease (AD) risk, to evaluate the potential impact of long-term exposure to corresponding therapeutics.MethodsWe conducted Mendelian randomization analyses using variants in genes that encode the protein targets of several approved lipid-lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encoding the target of mipomersen). Variants were weighted by associations with low-density lipoprotein cholesterol (LDL-C) using data from lipid genetics consortia (n up to 295,826). We meta-analyzed Mendelian randomization estimates for regional variants weighted by LDL-C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls).ResultsModels for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid-lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug target = 1.45, 95% confidence interval = 1.23-1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition.InterpretationWe did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for AD prevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9 inhibitors may be warranted. ANN NEUROL 2020;87:30-39.
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