Dataset Information

Causal effects between atrial fibrillation and heart failure: evidence from a bidirectional Mendelian randomization study.

ABSTRACT:

Background

Observational studies have suggested a close association between atrial fibrillation (AF) and heart failure (HF), yet the causal effect remains uncertain. In this study, we employed a bidirectional Mendelian randomization analysis to investigate the causal effect of one disease on the other.

Methods

Genetic instrumental variables were obtained from large-scale summary-level genome-wide association studies of AF (n = 1,030,836) and HF(n = 1,665,481), respectively. Two-sample Mendelian randomization was conducted to establish causal inferences. Inverse-variance weighted (IVW) was the primary estimate, while additional analyses including MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR-Egger, and Weighted median were performed to validate robustness and identify pleiotropy.

Results

After accounting for confounding variables, MR analysis suggested a potential causal relationship between AF and HF. An augmented genetic predisposition to atrial fibrillation was associated with an elevated risk of heart failure (odds ratio (OR) = 1.18, 95% confidence interval (CI):1.14-1.22). Likewise, genetically determined heart failure also increased the risk of heart failure (OR = 1.44, 95%CI:1.23-1.68). The robustness of the findings was corroborated through MR sensitivity analyses, and the causal estimates remained consistent when the instrument P-value threshold was tightened.

Conclusions

Our bidirectional Mendelian randomization study supports a reciprocal causal relationship between AF and HF. The shared genetic profile of these conditions may provide crucial insights into potential therapeutic targets for the prevention and progression of both disorders. These findings underscore the necessity for further investigation into the underlying molecular mechanisms linking AF and HF, as well as the potential for personalized treatment strategies grounded in genetic profiling.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC10424396 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Causal effects between atrial fibrillation and heart failure: evidence from a bidirectional Mendelian randomization study.

Zhang Zhuxin Z Li Le L Hu Zhao Z Zhou Likun L Zhang Zhenhao Z Xiong Yulong Y Yao Yan Y

BMC medical genomics 20230814 1

<h4>Background</h4>Observational studies have suggested a close association between atrial fibrillation (AF) and heart failure (HF), yet the causal effect remains uncertain. In this study, we employed a bidirectional Mendelian randomization analysis to investigate the causal effect of one disease on the other.<h4>Methods</h4>Genetic instrumental variables were obtained from large-scale summary-level genome-wide association studies of AF (n = 1,030,836) and HF(n = 1,665,481), respectively. Two-sa ...[more]

PMID: 37580781

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Project description:BackgroundHeart failure (HF) is a prevalent cardiac condition characterized by high mortality and morbidity rates. Immune cells play a pivotal role as crucial biomarkers in assessing the overall immune status of individuals. However, the causal relationship between circulating immune cells and the pathogenesis of HF remains an area requiring further investigation.ObjectivesThe aim of this study was to investigate the genetic interactions between circulating immune cells and HF, and to further elucidate the genetic associations between different lymphocyte subsets and HF.MethodsWe obtained genetic variants associated with circulating immune cells as instrumental variables (IVs) from the Blood Cell Consortium and publicly available HF summary data. We conducted additional subsets analyses on lymphocyte counts. Our study utilized two-sample and multivariate Mendelian randomization (MVMR) analysis to investigate the causal effect of immune cells on HF. The primary analysis employed inverse variance weighting (IVW) and was complemented by a series of sensitivity analyses.ResultsThe findings of the study showed that the IVW model demonstrated a significant correlation between an elevation in lymphocyte count and a decreased risk of HF (OR = 0.97, 95% CI, 0.94 - 1.00, P = 0.032). However, no such correlation was evident in the MVMR analysis for lymphocytes and HF. Furthermore, the examination of the lymphocyte subsets indicated that an increase in CD39+ CD4+ T-cell counts was notably linked to a reduced risk of HF (OR = 0.96, 95% CI, 0.95 - 0.98, P = 0.0002). The MVMR results confirmed that the association between CD39+ CD4+ T-cell counts and HF remained significant. There was no substantial evidence of reverse causality observed between circulating immune cells and HF.ConclusionOur MR research provided evidence for a causal relationship between lymphocyte cell and HF. Subsets analyses revealed a causal relationship between CD39+ CD4+ T lymphocytes and HF. These findings will facilitate a future understanding of the mechanisms underlying HF.

Project description:Background The knowledge gap regarding whether the correlation between atrial fibrillation (AF) and dementia in observational studies is causation or driven by other shared risk factors remains substantially unfilled. Methods and Results We performed a comprehensive 2-sample Mendelian randomization study to evaluate the causal effect of AF on overall dementia and its subtypes, including vascular dementia, Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. The primary results in inverse variance-weighted analyses were further validated by various Mendelian randomization sensitivity analyses. Additionally, we conducted multivariable Mendelian randomization to examine 10 candidate mediators of the causal association of AF and dementia. Genetic predisposition to AF was modestly associated with an increased risk of overall dementia (odds ratio, 1.140 [95% CI, 1.023-1.271]; P=0.018) and strongly associated with vascular dementia (odds ratio, 1.350 [95% CI, 1.076-1.695]; P=0.010). Genetically predicted AF indicated neutral effects on Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. In multivariable Mendelian randomization analysis, the total effect of AF on overall dementia was remarkably attenuated by adjusting for genetic effect for ischemic stroke (odds ratio, 1.068 [95% CI, 0.953-1.197]; P=0.259) and low cardiac output (odds ratio, 1.046 [95% CI, 0.926-1.181]; P=0.475), indicating that the causal association of genetically predicted AF with dementia was potentially mediated by ischemic stroke and low cardiac output. The causal effect of genetically predicted AF on dementia was independent of cerebral small-vessel disease and brain volume phenotypes. Conclusions Our findings provided novel evidence supporting the causal effect of genetically predicted AF on dementia mediated by ischemic stroke and low cardiac output. Future clinical trials are warranted to evaluate the potential role of appropriate AF management in dementia prevention.

Project description:Background: Traditional observational studies have demonstrated an association between heart failure and Alzheimer's disease. The strengths of observational studies lie in their speed of implementation, cost, and applicability to rare diseases. However, observational studies have several limitations, such as uncontrollable confounders. Therefore, we employed Mendelian randomization of genetic variants to evaluate the causal relationships existing between AD and HF, which can avoid these limitations. Materials and Methods: A two-sample bidirectional MR analysis was employed. All datasets were results from the UK's Medical Research Council Integrative Epidemiology Unit genome-wide association study database, and we conducted a series of control steps to select the most suitable single-nucleotide polymorphisms for MR analysis, for which five primary methods are offered. We reversed the functions of exposure and outcomes to explore the causal direction of HF and AD. Sensitivity analysis was used to conduct several tests to avoid heterogeneity and pleiotropic bias in the MR results. Results: Our MR studies did not support a meaningful causal relationship between AD on HF (MR-Egger, p = 0.634 > 0.05; weighted median (WM), p = 0.337 > 0.05; inverse variance weighted (IVW), p = 0.471 > 0.05; simple mode, p = 0.454 > 0.05; weighted mode, p = 0.401 > 0.05). At the same time, we did not find a significant causal relationship between HF and AD with four of the methods (MR-Egger, p = 0.195 > 0.05; IVW, p = 0.0879 > 0.05; simple mode, p = 0.170 > 0.05; weighted mode, p = 0.110 > 0.05), but the WM method indicated a significant effect of HF on AD (p = 0.025 < 0.05). Because the statistical powers of IVW and MR-Egger are more than that of WM, we think that there is no causal effect of HF on AD. Sensitivity analysis and horizontal pleiotropy were not detected in the MR analysis. Conclusion: Our results did not provide significant evidence indicating any causal relationships between HF and AD in the European population. Therefore, more large-scale datasets or datasets related to similar factors are expected for further MR analysis.

Dataset Information

Causal effects between atrial fibrillation and heart failure: evidence from a bidirectional Mendelian randomization study.

Background

Methods

Results

Conclusions

Publications

Causal effects between atrial fibrillation and heart failure: evidence from a bidirectional Mendelian randomization study.

Similar Datasets

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