Cardiometabolic risks of SARS-CoV-2 hospitalization using Mendelian Randomization.
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ABSTRACT:
SUBMITTER: Lorincz-Comi N
PROVIDER: S-EPMC8042041 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Individuals with a diagnosis of schizophrenia are known to be at high risk of premature mortality due to poor physical health, especially cardiovascular disease, diabetes, and obesity. The reasons for these physical health outcomes within this patient population are complex. Despite well-documented cardiometabolic adverse effects of certain antipsychotic drugs and lifestyle factors, schizophrenia may have an independent effect. Aims: To investigate if there is evidence that schizophrenia is causally related to cardiometabolic traits (blood lipids, anthropometric traits, glycaemic traits, blood pressure) and vice versa using bi-directional two-sample Mendelian randomization (MR) analysis. Methods: We used 185 genetic variants associated with schizophrenia from the latest Psychiatric Genomics Consortium GWAS (n = 130,644) in the forward analysis (schizophrenia to cardiometabolic traits) and genetic variants associated with the cardiometabolic traits from various consortia in the reverse analysis (cardiometabolic traits to schizophrenia), both at genome-wide significance (5 × 10-8). The primary method was inverse-variance weighted MR, supported by supplementary methods such as MR-Egger, as well as median and mode-based methods. Results: In the forward analysis, schizophrenia was associated with slightly higher low-density lipoprotein (LDL) cholesterol levels (0.013 SD change in LDL per log odds increase in schizophrenia risk, 95% CI, 0.001-0.024 SD; p = 0.027) and total cholesterol levels (0.013 SD change in total cholesterol per log odds increase in schizophrenia risk, 95% CI, 0.002-0.025 SD; p = 0.023). However, these associations did not survive multiple testing corrections. There was no evidence of a causal effect of cardiometabolic traits on schizophrenia in the reverse analysis. Discussion: Dyslipidemia and obesity in schizophrenia patients are unlikely to be driven primarily by schizophrenia itself. Therefore, lifestyle, diet, antipsychotic drugs side effects, as well as shared mechanisms for metabolic dysfunction and schizophrenia such as low-grade systemic inflammation could be possible reasons for the apparent increased risk of metabolic disease in people with schizophrenia. Further research is needed to examine the shared immune mechanism hypothesis.
| S-EPMC10115959 | biostudies-literature
Project description:Mendelian randomization (MR) is a burgeoning field that involves the use of genetic variants to assess causal relationships between exposures and outcomes. MR studies can be straightforward; for example, genetic variants within or near the encoding locus that is associated with protein concentrations can help to assess their causal role in disease. However, a more complex relationship between the genetic variants and an exposure can make findings from MR more difficult to interpret. In this Review, we describe some of these challenges in interpreting MR analyses, including those from studies using genetic variants to assess causality of multiple traits (such as branched-chain amino acids and risk of diabetes mellitus); studies describing pleiotropic variants (for example, C-reactive protein and its contribution to coronary heart disease); and those investigating variants that disrupt normal function of an exposure (for example, HDL cholesterol or IL-6 and coronary heart disease). Furthermore, MR studies on variants that encode enzymes responsible for the metabolism of an exposure (such as alcohol) are discussed, in addition to those assessing the effects of variants on time-dependent exposures (extracellular superoxide dismutase), cumulative exposures (LDL cholesterol), and overlapping exposures (triglycerides and non-HDL cholesterol). We elaborate on the molecular features of each relationship, and provide explanations for the likely causal associations. In doing so, we hope to contribute towards more reliable evaluations of MR findings.
| S-EPMC5600813 | biostudies-literature
Project description:Genome-wide association studies, which typically report regression coefficients summarizing the associations of many genetic variants with various traits, are potentially a powerful source of data for Mendelian randomization investigations. We demonstrate how such coefficients from multiple variants can be combined in a Mendelian randomization analysis to estimate the causal effect of a risk factor on an outcome. The bias and efficiency of estimates based on summarized data are compared to those based on individual-level data in simulation studies. We investigate the impact of gene-gene interactions, linkage disequilibrium, and 'weak instruments' on these estimates. Both an inverse-variance weighted average of variant-specific associations and a likelihood-based approach for summarized data give similar estimates and precision to the two-stage least squares method for individual-level data, even when there are gene-gene interactions. However, these summarized data methods overstate precision when variants are in linkage disequilibrium. If the P-value in a linear regression of the risk factor for each variant is less than 1×10??, then weak instrument bias will be small. We use these methods to estimate the causal association of low-density lipoprotein cholesterol (LDL-C) on coronary artery disease using published data on five genetic variants. A 30% reduction in LDL-C is estimated to reduce coronary artery disease risk by 67% (95% CI: 54% to 76%). We conclude that Mendelian randomization investigations using summarized data from uncorrelated variants are similarly efficient to those using individual-level data, although the necessary assumptions cannot be so fully assessed.
| S-EPMC4377079 | biostudies-other
Project description:Although a large body of literature reported that high intake of vitamin E played a possible role in reducing risk of cardiometabolic diseases, conflicting results were also found in some observational studies due to confounding factors. Hence, we used a Mendelian randomization study as an alternative way to examine the causality between circulating vitamin E and cardiometabolic diseases. Summary-level data were extracted from consortia and three single nucleotide polymorphisms were used as instrumental variables. Our study showed that a one-SD increase in circulating vitamin E levels was causally associated with an increased risk of coronary artery disease [odds ratio (OR) 3.16 (95%CI 1.74, 5.73); p = 1.91 × 10-3] at the Bonferroni-adjusted level of significance (p<0.005). Moreover, a one-SD increase in circulating vitamin E levels was associated with a 0.572-SD increase in low density lipoprotein cholesterol (mg/dl), a 0.693-SD increase in total cholesterol (mg/dl), and a 1.45-SD increase in triglyceride (mg/dl), but a 0.502-SD decrease in high density lipoprotein cholesterol (mg/dl) at the Bonferroni-adjusted level of significance (p<0.0028). Our findings indicated that genetically elevated vitamin E was associated with increased risk of coronary artery disease, suggesting an adverse causality between circulating vitamin E and coronary artery disease.
| S-EPMC6769411 | biostudies-literature
Project description:BackgroundAlthough many observational studies have demonstrated significant relationships between obesity and cardiometabolic traits, the causality of these relationships in East Asians remains to be elucidated.MethodsWe conducted individual-level Mendelian randomization (MR) analyses targeting 14,083 participants in the Japan Multi-Institutional Collaborative Cohort Study and two-sample MR analyses using summary statistics based on genome-wide association study data from 173,430 Japanese. Using 83 body mass index (BMI)-related loci, genetic risk scores (GRS) for BMI were calculated, and the effects of BMI on cardiometabolic traits were examined for individual-level MR analyses using the two-stage least squares estimator method. The β-coefficients and standard errors for the per-allele association of each single-nucleotide polymorphism as well as all outcomes, or odds ratios with 95% confidence intervals were calculated in the two-sample MR analyses.ResultsIn individual-level MR analyses, the GRS of BMI was not significantly associated with any cardiometabolic traits. In two-sample MR analyses, higher BMI was associated with increased risks of higher blood pressure, triglycerides, and uric acid, as well as lower high-density-lipoprotein cholesterol and eGFR. The associations of BMI with type 2 diabetes in two-sample MR analyses were inconsistent using different methods, including the directions.ConclusionThe results of this study suggest that, even among the Japanese, an East Asian population with low levels of obesity, higher BMI could be causally associated with the development of a variety of cardiometabolic traits. Causality in those associations should be clarified in future studies with larger populations, especially those of BMI with type 2 diabetes.
| S-EPMC10751192 | biostudies-literature
Project description:BackgroundThe association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.Methods and findingsWe used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n? =? 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p? = ?0.001).ConclusionsWe provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
| S-EPMC3692470 | biostudies-literature
Project description:Observational evidence links higher blood levels of copper with higher risk of cardiovascular diseases. However, whether those associations reflect causal links or can be attributed to confounding is still not fully clear. We investigated causal effects of copper on the risk of cardiometabolic endpoints (stroke, coronary artery disease [CAD] and type 2 diabetes) and cardiometabolic risk factors in two-sample Mendelian randomization (MR) studies. The selection of genetic instruments for blood copper levels relied on meta-analysis of genome-wide association studies in three independent studies (European Prospective Investigation into Cancer and Nutrition-Potsdam study, Prospective investigation of the Vasculature in Uppsala Seniors study, Queensland Institute of Medical Research studies). For the selected instruments, outcome associations were drawn from large public genetic consortia on the respective disease endpoints (MEGASTROKE, Cardiogram, DIAGRAM) and cardiometabolic risk factors. MR results indicate an inverse association for genetically higher copper levels with risk of CAD (odds ratio [95% confidence interval] = 0.92 [0.86-0.99], P = 0.022) and systolic blood pressure (beta [standard error (SE)] = -0.238 [0.121]; P = 0.049). Multivariable MR incorporating copper and systolic blood pressure into one model suggested systolic blood pressure as mediating factor between copper and CAD risk. In contrast to previous observational evidence establishing higher blood copper levels as risk-increasing factor for cardiometabolic diseases, this study suggests that higher levels of genetically predicted copper might play a protective role for the development of CAD and systolic blood pressure.
| S-EPMC8895748 | biostudies-literature
Project description:Background: Although some observational studies have shown that physical activity may have a positive relationship with cardiovascular diseases, the causal effect remains uncertain. We conducted a Mendelian randomization (MR) study to identify the potential causal effect between physical activity and cardiovascular diseases. Methods: Summary statistics of genome-wide association studies on four physical activity phenotypes and cardiovascular diseases were utilized. MR analysis was performed using inverse-variance weighted (IVW) and multivariable MR. Multiple sensitivity analysis was further conducted to identify the robustness of our results. Results: Genetically predicted self-reported vigorous physical activity (VPA) was significantly associated with lower risk of myocardial infarction (IVW OR: 0.24, 95% CI: 0.08–0.68, p-value: 0.007). Additionally, the causal effect of VPA with myocardial infarction was robust after adjusting for several cardiovascular risk factors through using the multivariable MR. There were no apparent causal associations between physical activity with other cardiovascular diseases. Results were consistent with the sensitivity analysis. Conclusion: The present study supports a protective role of self-reported vigorous physical activity in the initiation of myocardial infarction and highlights the importance of activity levels of physical activity. Further studies are required to elucidate the potential biological pathways of physical activity with cardiovascular diseases.
| S-EPMC8511639 | biostudies-literature
Project description:ObjectivesThis study aimed at estimating the SARS-CoV-2 infection hospitalization (IHR) and infection fatality ratios (IFR) in France.Patients and methodsA serosurvey was conducted in 9782 subjects from the two French regions with the highest incidence of COVID-19 during the first wave of the pandemic and coupled with surveillance data.ResultsIHR and IFR were 2.7% and 0.49% overall. Both were higher in men and increased exponentially with age. The relative risks of hospitalization and death were 2.1 (95% CI: 1.9-2.3) and 3.8 (2.4-4.2) per 10-year increase, meaning that IHR and IFR approximately doubled every 10 and 5 years, respectively. They were dramatically high in the very elderly (80-90 years: IHR: 26%, IFR: 9.2%), and also substantial in younger adults (40-50 years: IHR: 0.98%, IFR: 0.042%).ConclusionsThese findings support the need for comprehensive preventive measures to help reduce the spread of the virus, even in young or middle-aged adults.
| S-EPMC7836556 | biostudies-literature
Project description: Not available
| S-EPMC8611483 | biostudies-literature