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Objective: Observational studies have indicated an association between coffee consumption and amyotrophic lateral sclerosis (ALS). Nevertheless, whether the association is causal is still unclear. We conducted a Mendelian randomiz...
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Objective: Observational studies have indicated an association between coffee consumption and amyotrophic lateral sclerosis (ALS). Nevertheless, whether the association is causal is still unclear. We conducted a Mendelian randomization study to explore whether coffee consumption is causally related to ALS. Methods: Two genome-wide association studies (GWASs) investigating coffee consumption (n = 129,422 and 375,833, respectively) were adopted to define instrumental variables for coffee consumption (high vs. infrequent/no, 1 cup/day increase, and 50% increase). Summary-level data for ALS were adopted from a large GWAS of ALS with a total of 20,806 cases and 59,804 controls. Results: Genetically predicted higher coffee consumption was not associated with ALS. The ORs were 1.02 (95% CI: 0.93-1.13; p = 0.649) for high vs. infrequent/no, 0.98 (95% CI: 0.84-1.15; p = 0.822) for 1 cup/day increase, 0.97 (95% CI: 0.79-1.19; p = 0.766) for 50% increase. Sensitivity analyses yielded consistent results. No pleiotropic bias and heterogeneity were observed. Conclusion: Using multiple approaches and sensitivity analyses, our MR results show that genetically predicted coffee consumption was not associated with ALS. Further studies are warranted to explore the effect of coffee consumption on ALS progression.
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Background: Mendelian randomization (MR) is a powerful tool in epidemiology that can be used to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilizing genetic variants that ...
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Background: Mendelian randomization (MR) is a powerful tool in epidemiology that can be used to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilizing genetic variants that are instrumental variables (IVs) for the exposure. This has been extended to multivariable MR (MVMR) to estimate the effect of two or more exposures on an outcome.
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In this study, we examined whether C-reactive protein (CRP) play causal roles in Alzheimer's disease (AD) using Mendelian randomization (MR) analysis. Summary-level data for AD (71,880 cases and 383,378 controls) was obtained from...
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In this study, we examined whether C-reactive protein (CRP) play causal roles in Alzheimer's disease (AD) using Mendelian randomization (MR) analysis. Summary-level data for AD (71,880 cases and 383,378 controls) was obtained from the large meta-analyses of genome-wide association studies. As instrumental variables, we used 56 single nucleotide polymorphisms (n = 4 for conservative CRP instruments; n = 52 for liberal CRP instruments), previously identified to be associated with CRP levels (n = 194,418 and 204,402 European individuals, respectively). MR estimates were calculated using the inverse-variance weighted approach and complemented with the weighted median, MR-PRESSO, and MR-Egger methods. Genetically predicted elevated CRP levels were significantly associated with an increased risk of AD (conservative CRP instruments: odds ratio, 1.02; 95% CI, 1.01-1.04; p = 0.008). Results for liberal CRP instruments showed a consistent trend. Sensitivity analyses generated similar results and no pleiotropic bias was observed. This study indicates that genetically predicted elevated CRP levels may be a causal risk factor for AD. (c) 2021 Elsevier Inc. All rights reserved.
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Symptoms related with gastro-esophageal reflux disease (GERD) were previously shown to be linked with increased risk for the 2019 coronavirus disease (COVID-19). We aim to interrogate the possibility of a shared genetic basis betw...
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Symptoms related with gastro-esophageal reflux disease (GERD) were previously shown to be linked with increased risk for the 2019 coronavirus disease (COVID-19). We aim to interrogate the possibility of a shared genetic basis between GERD and COVID-19 outcomes. Using published GWAS data for GERD (78 707 cases; 288 734 controls) and COVID-19 susceptibility (up to 32 494 cases; 1.5 million controls), we examined the genetic relationship between GERD and three COVID-19 outcomes: risk of developing severe COVID-19, COVID-19 hospitalization and overall COVID-19 risk. We estimated the genetic correlation between GERD and COVID-19 outcomes followed by Mendelian randomization (MR) analyses to assess genetic causality. Conditional analyses were conducted to examine whether known COVID-19 risk factors (obesity, smoking, type-II diabetes, coronary artery disease) can explain the relationship between GERD and COVID-19. We found small to moderate genetic correlations between GERD and COVID-19 outcomes (rg between 0.06 and 0.24). MR analyses revealed a OR of 1.15 (95% CI: 0.96-1.39) for severe COVID-19; 1.16 (1.01-1.34) for risk of COVID-19 hospitalization; 1.05 (0.97-1.13) for overall risk of COVID-19 per doubling of odds in developing GERD. The genetic correlation/associations between GERD and COVID-19 showed mild attenuation towards the null when obesity and smoking was adjusted for. Susceptibility for GERD and risk of COVID-19 hospitalization were genetically correlated, with MR findings supporting a potential causal role between the two. The genetic association between GERD and COVID-19 was partially attenuated when obesity is accounted for, consistent with obesity being a major risk factor for both diseases.
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Background—Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong associat...
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Background—Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis. Methods and Results—Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in 4 prospective and 14 case–control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression (P=5.1×10?6). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95% confidence intervals [?0.9%, 1.6%]; P=0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P=0.20). Conclusions—This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.
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The strong evidence for benefits of low-density lipoprotein cholesterol (LDL-C) lowering has made it a mainstay of primary and secondary prevention. Recent large-scale studies have identified functional variants in key genes, such...
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The strong evidence for benefits of low-density lipoprotein cholesterol (LDL-C) lowering has made it a mainstay of primary and secondary prevention. Recent large-scale studies have identified functional variants in key genes, such as lipoprotein lipase (LPL)1 or its inhibitor ANGPTL4, that lower triglyceride levels and decrease risk of coronary disease, leading to a renewed focus on triglyceride-lowering therapies. Mendelian randomization studies can examine causal lipid-lowering treatment pathways and can offer a powerful study design to bridge treatment knowledge gaps.
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The aim of this study was to explore the application of Mendelian randomization (MR) Egger and inverse variance weighted (IVW) in a causal effect on depression and ankylosing spondylitis (AS). Instrumental variables (IVs) were det...
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The aim of this study was to explore the application of Mendelian randomization (MR) Egger and inverse variance weighted (IVW) in a causal effect on depression and ankylosing spondylitis (AS). Instrumental variables (IVs) were determined using genome-wide association studies. The 2-sample MR analysis was conducted by MR Egger to test the causal effect between depression and AS. The pleiotropy of potential instrumental variables was evaluated. The results of MR Egger and IVW were further compared. A total of 3 single nucleotide polymorphisms as the construct IVs were included. IVW results showed a significant causal effect between depression and AS ( P .05). It was also suggested that there was no horizontal pleiotropy in IVs (MR Egger intercept: ?0.0004, P = .471). Reverse MR analysis suggested that there was no causal effect between AS and depression ( P > .05). Gene expression quantitative trait locus (QTLs) suggested that rs2517601 and RNF39 were positively correlated (beta = 1.066, P < .001). Depression may be one of the causes of AS by MR analysis in a European population. We can estimate the causal effect based on IVW when horizontal pleiotropy is very tiny.
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? 2022 The Author(s)Background: Coffee contains many bioactive chemicals and associations with cancer have been reported in observational studies. In this Mendelian randomisation (MR) study we investigated the causal associations ...
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? 2022 The Author(s)Background: Coffee contains many bioactive chemicals and associations with cancer have been reported in observational studies. In this Mendelian randomisation (MR) study we investigated the causal associations of coffee consumption with a broad range of cancers. Materials and methods: Twelve independent genetic variants proxied coffee consumption. Genetically-predicted risk of any cancer (59,647 cases) and 22 site-specific cancers was estimated in European-descent individuals in UK Biobank. Univariable and multivariable MR analyses were conducted. Results: Genetically-predicted coffee consumption was not associated with risk of any cancer in the main analysis (OR 1.05, 95% CI 0.98–1.14, p = 0.183) but was associated with an increased risk of digestive system cancer (OR 1.28, 95% CI 1.09–1.51, p = 0.003), driven by a strong association with oesophageal cancer (OR 2.79, 95% CI 1.73–4.50, p = 2.5×10?5). This association was consistent after adjustment for genetically-predicted body mass index, smoking and alcohol consumption. There was no strong evidence supporting a causal relationship between genetically-predicted coffee consumption and the majority of cancers studied. However, genetically-predicted coffee consumption was associated with increased risk of multiple myeloma (OR 2.25, 95% CI 1.30–3.89, p = 0.004) and reduced ovarian cancer risk (OR 0.63, 95% CI 0.43–0.93, p = 0.020). Conclusions: This MR study provides strong support for a causal association of coffee consumption with oesophageal cancer, but not for the majority of cancer types, and the underlying mechanisms require investigation.
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