scholarly journals Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Wuqing Huang ◽  
Jun Xiao ◽  
Jianguang Ji ◽  
Liangwan Chen
Keyword(s):  
Target Genes ◽  
Ldl Cholesterol ◽  
Viral Infections ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Positive Association ◽  
Lipid Lowering ◽  
Technology Program ◽  
Lipid Lowering Drugs ◽  
Mr Study

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 2-sample Mendelian Randomization (MR) study. Methods: We used two kinds of genetic instruments to proxy the exposure of lipid-lowering drugs, including eQTLs of drugs target genes, and genetic variants within or nearby drugs target genes associated with LDL cholesterol from GWAS. 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). 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 2-sample MR study suggested a potential causal relationship between HMGCR inhibition and the reduced risk of COVID-19 hospitalization. Funding: Fujian Province Major Science and Technology Program.

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

2021 ◽  
Author(s):  
Wuqing Huang ◽  
Jun Xiao ◽  
Jianguang Ji ◽  
Liang-Wan Chen
Keyword(s):  
Target Genes ◽  
Genome Wide Association Study ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Severe Disease ◽  
Lipid Lowering ◽  
Pcsk9 Inhibitors ◽  
Lipid Lowering Drugs ◽  
Mr Study

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.

scholarly journals Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

2021 ◽  
Author(s):  
Shuai Yuan ◽  
Maria Bruzelius ◽  
Susanna C. Larsson
Keyword(s):  
Renal Function ◽  
Venous Thromboembolism ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Increased Risk ◽  
Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

scholarly journals Causal Effect Between Total Cholesterol and HDL Cholesterol as Risk Factors for Chronic Kidney Disease: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Liu Miao ◽  
Yan Min ◽  
Chuan-Meng Zhu ◽  
Jian-Hong Chen ◽  
Bin Qi ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Serum Lipid ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Hdl Cholesterol ◽  
Causal Effects ◽  
Lipid Levels ◽  
Serum Lipid Levels ◽  
Genome Wide ◽  
Mr Study

Abstract Background/Aims: While observational studies show an association between serum lipid levels and cardiovascular disease (CVD), intervention studies that examine the preventive effects of serum lipid levels on the development of CKD are lacking. Methods: To estimate the role of serum lipid levels in the etiology of CKD, we conducted a two-sample Mendelian randomization (MR) study on serum lipid levels. Single nucleotide polymorphisms (SNPs), which were significantly associated genome-wide with plasma serum lipid levels from the GLGC and CKDGen consortium genome-wide association study (GWAS), including total cholesterol (TC, n = 187365), triglyceride (TG, n = 177861), HDL cholesterol (HDL-C, n = 187167), LDL cholesterol (LDL-C, n = 173082), apolipoprotein A1 (ApoA1, n = 20687), apolipoprotein B (ApoB, n = 20690) and CKD (n = 117165), were used as instrumental variables. None of the lipid-related SNPs was associated with CKD (all P > 0.05). Results: MR analysis genetically predicted the causal effect between TC/HDL-C and CKD. The odds ratio (OR) and 95% confidence interval (CI) of TC within CKD was 0.756 (0.579 to 0.933) (P = 0.002), and HDL-C was 0.85 (0.687 to 1.012) (P = 0.049). No causal effects between TG, LDL-C- ApoA1, ApoB and CKD were observed. Sensitivity analyses confirmed that TC and HDL-C were significantly associated with CKD. Conclusions: The findings from this MR study indicate causal effects between TC, HDL-C and CKD. Decreased TC and elevated HDL-C may reduce the incidence of CKD but need to be further confirmed by using a genetic and environmental approach.

scholarly journals The effect of plasma lipids and lipid lowering interventions on bone mineral density: a Mendelian randomization study

2018 ◽  
Author(s):  
Jie Zheng ◽  
Marie-Jo Brion ◽  
John P. Kemp ◽  
Nicole M. Warrington ◽  
Maria-Carolina Borges ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Standard Deviation ◽  
Bone Mineral ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Lipid Levels ◽  
Mineral Density

AbstractStatin treatment increases bone mineral density (BMD) and reduces fracture risk, but the underlying mechanism is unclear. We used Mendelian randomization (MR) to assess whether this relation is explained by a specific effect in response to statin use, or by a general effect of lipid-lowering. We utilized 400 single nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels and results from a heel BMD GWAS (derived from quantitative ultrasound) in 426,824 individuals from the UK Biobank. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride levels on BMD. To test whether the effect of statins on BMD was mediated by lowering lipid levels, MR was repeated with and without SNPs in theHMGCRregion, the gene targeted by statins. Univariate MR analyses provided evidence for a causal effect of LDL-C on BMD (β= −0.060; −0.084 to −0.036; P = 4×10-6; standard deviation change in BMD per standard deviation change in LDL-C, with 95% CI), but not HDL or triglycerides. Multivariable MR analysis suggested that the effect of LDL-C on BMD was independent of HDL-C and triglycerides, and sensitivity analyses involving MR Egger and weighted median MR approaches suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in theHMGCRregion showed similar effects on BMD(β= −0.083; −0.132 to −0.034; P = 0.001) to those excluding these SNPs (β= −0.063; −0.090 to −0.036; P = 8×10-6). Bidirectional MR analyses provided some evidence for a causal effect of BMD on plasma LDL-C levels. Our results suggest that effects of statins on BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis.

scholarly journals Bipolar disorder and cannabis use: a bidirectional two-sample Mendelian randomization study

2020 ◽  
Author(s):  
Oskar Hougaard Jefsen ◽  
Maria Speed ◽  
Doug Speed ◽  
Søren Dinesen Østergaard
Keyword(s):  
Bipolar Disorder ◽  
Standard Deviation ◽  
Odds Ratio ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Cannabis Use ◽  
Genome Wide ◽  
Log Odds ◽  
The Relationship ◽  
Mr Study

AbstractAimsCannabis use is associated with a number of psychiatric disorders, however the causal nature of these associations has been difficult to establish. Mendelian randomization (MR) offers a way to infer causality between exposures with known genetic predictors (genome-wide significant single nucleotide polymorphisms (SNPs)) and outcomes of interest. MR has previously been applied to investigate the relationship between lifetime cannabis use (having ever used cannabis) and schizophrenia, depression, and attention-deficit / hyperactivity disorder (ADHD), but not bipolar disorder, representing a gap in the literature.MethodsWe conducted a two-sample bidirectional MR study on the relationship between bipolar disorder and lifetime cannabis use. Genetic instruments (SNPs) were obtained from the summary statistics of recent large genome-wide association studies (GWAS). We conducted a two-sample bidirectional MR study on the relationship between bipolar disorder and lifetime cannabis use, using inverse-variance weighted regression, weighted median regression and Egger regression.ResultsGenetic liability to bipolar disorder was significantly associated with an increased risk of lifetime cannabis use: scaled log-odds ratio (standard deviation) = 0.0174 (0.039); P-value = 0.00001. Genetic liability to lifetime cannabis use showed no association with the risk of bipolar disorder: scaled log-odds ratio (standard deviation) = 0.168 (0.180); P-value = 0.351. The sensitivity analyses showed no evidence for pleiotropic effects.ConclusionsThe present study finds evidence for a causal effect of liability to bipolar disorder on the risk of using cannabis at least once. No evidence was found for a causal effect of liability to cannabis use on the risk of bipolar disorder. These findings add important new knowledge to the understanding of the complex relationship between cannabis use and psychiatric disorders.

scholarly journals Major depressive disorder but not bipolar disorder and schizophrenia is a causal factor for type 2 diabetes as determined by Mendelian randomization

2020 ◽  
Author(s):  
Heejin Jin ◽  
Jeewon Lee ◽  
Oh Sohee ◽  
Sanghun Lee ◽  
Sungho Won
Keyword(s):  
Type 2 Diabetes ◽  
Bipolar Disorder ◽  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Reverse Causality ◽  
Major Depressive ◽  
Mr Study

Objective: In many epidemiologic studies, type 2 diabetes has been reported to be associated with severe mental illness (SMI) such as schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD). However, the relationship between SMI and type 2 diabetes is bi-directional, and the causal relationship remains unclear due to various confounders. Therefore, a Mendelian randomization (MR) study is necessary to identify the causality between them. Research Design and Methods: We conducted a two−sample MR study to identify the causal effect of SMI on type 2 diabetes using the inverse-variance weighted (IVW), MR−Egger, MR− Egger with a simulation extrapolation, weighted median approach, and MR-Pleiotropy RESidual Sum and Outlier methods. The most appropriate method was selected according to the instrument variables assumption. Results: We found that MDD had a significant causal effect on type 2 diabetes from the results obtained using the IVW method (Odds ratio (OR): 1.191, 95% CI: 1.036−1.372, P = 0.014); however, this was not observed for BPD (IVW, OR: 1.006, 95% CI: 0.918−1.104, P = 0.892) or SCZ (IVW, OR: 1.016, 95% CI: 0.974−1.059, P = 0.463). The absence of reverse-causality between MDD and type 2 diabetes was also demonstrated from bidirectional MR studies. Conclusions: These results clearly reveal important knowledge on the causal role of MDD in the risk of type 2 diabetes without a residual confounding, whereas the causality of BPD and SCZ was not shown. Therefore, careful attention should be paid to MDD patients in type 2 diabetes prevention and treatment.

scholarly journals IMPACT OF ELEVATED PCSK9 LEVELS ON REGULATION OF LDL-CHOLESTEROL AFTER STATIN TREATMENT: STUDY WITH DIFFERENT TYPES OF LIPID LOWERING DRUGS

2011 ◽  
Vol 57 (14) ◽  
pp. E577
Author(s):  
Masa-aki Kawashiri ◽  
Atsushi Nohara ◽  
Tohru Noguchi ◽  
Hayato Tada ◽  
Akihiro Inazu ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Statin Treatment ◽  
Lipid Lowering ◽  
Lipid Lowering Drugs ◽  
Different Types

scholarly journals Cardiovascular outcomes trials with non-statin lipid-lowering drugs in diabetes

2018 ◽  
Vol 18 (3) ◽  
pp. 101-105
Author(s):  
Fariha Naeem ◽  
Gerard McKay ◽  
Miles Fisher
Keyword(s):  
Statin Therapy ◽  
Cardiovascular Events ◽  
Ldl Cholesterol ◽  
Lipid Lowering ◽  
High Dose ◽  
Large Trial ◽  
Pcsk9 Inhibitors ◽  
Vascular Events ◽  
Lipid Lowering Drugs ◽  
Cardiovascular Morbidity And Mortality

Statin therapy is proven to reduce cardiovascular morbidity and mortality in people with diabetes, and high-dose statins are recommended for people with established atherosclerotic vascular disease. In two dedicated studies in people with diabetes, fibrates did not significantly reduce cardiovascular events and were associated with serious side effects. A similar lack of benefit was seen in two large studies of niacin. Ezetimibe, when added to statins, may further reduce LDL cholesterol and non-fatal vascular events. The PCSK9 inhibitors are a new class of subcutaneous lipid- lowering drugs which cause profound reductions in LDL cholesterol when added to statins. Evolocumab reduced non-fatal cardiovascular events when added to background statin therapy in a larger group of subjects and the benefits were confirmed in a diabetes subgroup. In another large trial alirocumab reduced major adverse cardiovascular events and total mortality. The clinical use of ezetimibe and PCSK9 inhibitors is currently limited by cost.

scholarly journals Causal Effect Between Total Cholesterol and Hdl Cholesterol as Risk Factors for Chronic Kidney Disease: A Mendelian Randomization Study

2020 ◽  
Author(s):  
Liu Miao ◽  
Yan Min ◽  
Chuan-Meng Zhu ◽  
Jian-Hong Chen ◽  
Bin Qi ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Serum Lipid ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Hdl Cholesterol ◽  
Causal Effects ◽  
Lipid Levels ◽  
Serum Lipid Levels ◽  
Genome Wide ◽  
Mr Study

Abstract Background While observational studies show an association between serum lipid levels and cardiovascular disease (CVD), intervention studies that examine the preventive effects of serum lipid levels on the development of CKD are lacking. Methods To estimate the role of serum lipid levels in the etiology of CKD, we conducted a two-sample Mendelian randomization (MR) study on serum lipid levels. Single nucleotide polymorphisms (SNPs), which were significantly associated genome-wide with plasma serum lipid levels from the GLGC and CKDGen consortium genome-wide association study (GWAS), including total cholesterol (TC, n = 187365), triglyceride (TG, n = 177861), HDL cholesterol (HDL-C, n = 187167), LDL cholesterol (LDL-C, n = 173082), apolipoprotein A1 (ApoA1, n = 20687), apolipoprotein B (ApoB, n = 20690) and CKD (n = 117165), were used as instrumental variables. None of the lipid-related SNPs was associated with CKD (all P > 0.05). Results MR analysis genetically predicted the causal effect between TC/HDL-C and CKD. The odds ratio (OR) and 95% confidence interval (CI) of TC within CKD was 0.756 (0.579 to 0.933) (P = 0.002), and HDL-C was 0.85 (0.687 to 1.012) (P = 0.049). No causal effects between TG, LDL-C- ApoA1, ApoB and CKD were observed. Sensitivity analyses confirmed that TC and HDL-C were significantly associated with CKD. Conclusions The findings from this MR study indicate causal effects between TC, HDL-C and CKD. Decreased TC and elevated HDL-C may reduce the incidence of CKD but need to be further confirmed by using a genetic and environmental approach.

scholarly journals Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled Mendelian randomization investigation

2019 ◽  
Author(s):  
Elias Allara ◽  
Gabriele Morani ◽  
Paul Carter ◽  
Apostolos Gkatzionis ◽  
Verena Zuber ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Aortic Stenosis ◽  
Aortic Valve Stenosis ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Cardiovascular Outcomes ◽  
Lipid Lowering ◽  
Abdominal Aortic

ABSTRACTAimsTo systematically investigate causal relationships between circulating lipids and cardiovascular outcomes, using a Mendelian randomization approach.Methods and ResultsIn the primary analysis, we performed two-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188,577 participants, and genetic associations with cardiovascular outcomes from 367,703 participants in UK Biobank.For LDL-cholesterol, in addition to the expected positive associations with coronary artery disease (CAD) risk (odds ratio per 1 standard deviation increase [OR], 1.45; 95% confidence interval [95%CI] 1.35-1.57) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically-predicted LDL-cholesterol with abdominal aortic aneurysm (OR 1.75; 95%CI 1.40-2.17), and aortic valve stenosis (OR 1.46; 95%CI 1.25-1.70). Genetically-predicted triglyceride levels were positively associated with CAD (OR 1.25; 95%CI 1.12-1.40), aortic valve stenosis (OR 1.29; 95%CI 1.04-1.61), and hypertension (OR 1.17; 95%CI 1.07-1.27), but inversely associated with venous thromboembolism (OR 0.79; 95%CI 0.67-0.93). The positive associations of genetically-predicted LDL-cholesterol and triglycerides with heart failure and aortic stenosis appeared to be mediated by CAD.ConclusionLowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis, but may increase risk of thromboembolism.

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