Mendelian randomization study on atrial fibrillation and cardiovascular disease subtypes.
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ABSTRACT:
SUBMITTER: Kwok MK
PROVIDER: S-EPMC8455674 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Several works of observational clinical research indicate that coronary artery disease (CAD) and atrial fibrillation (AF) aggravate each other. However, it is unknown whether these associations reveal independent causal processes. Objective: The present study aimed to evaluate causal associations between CAD and AF using two-sample Mendelian randomization (TSMR) analysis. Methods: Summary-level Genome-wide association study (GWAS) data for CAD were obtained from the CARDIoGRAMplusC4D consortium, including 60,801 patients and 123,504 controls. General data for AF were acquired from the largest meta-analysis, comprising of 60,620 patients with AF and 970,216 non-cases. After data harmonization, three different methods—inverse-variance weighted (IVW), MR-Egger, and weighted-median—were applied for TSMR analysis. Results: The calculated ORs (95% CIs) for AF using IVW, MR-Egger, and weighted-median analysis were 1.11 (1.05, 1.17; p-value < 0.001), 1.14 (1.00, 1.29; p-value = 0.049), and 1.13 (1.08, 1.19; p-value < 0.001), respectively; for CAD, the results were 1.01 (0.97, 1.04; p-value = 0.76), 0.95 (0.89, 1.02; p-value = 0.15), and 1.00 (0.95, 1.05; p-value = 0.97). Conclusion: This comprehensive TSMR analysis provides evidence that patients with CAD are associated with an increased risk of AF. However, no causal association was found between patients with AF and the risk of CAD. These findings benefit clinical decision-making. Early heart-rhythm monitoring should be performed in patients with CAD. The prevention and treatment of AF complications such as thrombosis may be essential to reduce the incidence of CAD in AF patients.
| S-EPMC8949548 | biostudies-literature
Project description:AimsIncreases in fat-free mass and fat mass have been associated with higher risk of atrial fibrillation (AF) in observational studies. It is not known whether these associations reflect independent causal processes. Our aim was to evaluate independent causal roles of fat-free mass and fat mass on AF.Methods and resultsWe conducted a large observational study to estimate the associations between fat-free mass and fat mass on incident AF in the UK Biobank (N = 487 404, N events = 10 365). Genome-wide association analysis was performed to obtain genetic instruments for Mendelian randomization (MR). We evaluated the causal effects of fat-free mass and fat mass on AF with two-sample method by using genetic associations from AFGen consortium as outcome. Finally, we evaluated independent causal effects of fat-free mass and fat mass with multivariate MR. Both fat-free mass and fat mass had observational associations with incident AF [hazard ratio (HR) = 1.77, 95% confidence interval (CI) 1.72-1.83; HR = 1.40, 95% CI 1.37-1.43 per standard deviation increase in fat-free and fat mass, respectively]. The causal effects using the inverse-variance weighted method were 1.55 (95% CI 1.38-1.75) for fat-free mass and 1.30 (95% CI 1.17-1.45) for fat mass. Weighted median, Egger regression, and penalized methods showed similar estimates. The multivariate MR analysis suggested that the causal effects of fat-free and fat mass were independent of each other (causal risk ratios: 1.37, 95% CI 1.06-1.75; 1.28, 95% CI 1.03-1.58).ConclusionGenetically programmed increases in fat-free mass and fat mass independently cause an increased risk of AF.
| S-EPMC6475522 | biostudies-literature
Project description:Atrial fibrillation (AF) patients have enlarged left atria (LA), but prior studies suggested enlarged atria as both cause and consequence of AF. The aim of this study is to investigate the causal association between AF and LA size and function. In the UK Biobank, all individuals with contoured cardiovascular magnetic resonance data were selected. LA maximal volume (LA max), LA minimal volume (LA min), LA stroke volume and LA ejection fraction were measured and indexed to body surface area (BSA). Two-sample Mendelian randomization analyses were performed using 84 of the known genetic variants associated with AF to assess the association with all LA size and function in individuals without prevalent AF. A total of 4274 individuals (mean age 62.0 ± 7.5 years, 53.2% women) were included. Mendelian randomization analyses estimated a causal effect between genetically determined AF and BSA-indexed LA max, LA min, and LA ejection fraction, but not between AF and LA stroke volume. Leave-one-out analyses showed that the causal associations were attenuated after exclusion of rs67249485, located near PITX2 gene. Our results suggest that AF causally increases LA size and decreases LA ejection fraction. The AF risk allele of rs67249485, located near the PITX2 gene, contributes strongly to these associations.
| S-EPMC8055882 | biostudies-literature
Project description:Background Atrial fibrillation (AF) has been shown to be associated with an increased risk of dementia as well as Alzheimer disease in observational studies. Whether this association reflects causal association is still unclear. The purpose of this study was to examine the causal association of AF with Alzheimer disease. Methods and Results We used a 2-sample Mendelian randomization approach to evaluate the causal effect of AF on Alzheimer disease. Summary data on the association of single nucleotide polymorphisms with AF were obtained from a recently published genome-wide association study with up to 1 030 836 individuals and data on single nucleotide polymorphism-Alzheimer disease association from another genome-wide association study with up to 455 258 individuals. AF was mainly diagnosed according to International Classification of Diseases, Ninth Revision (ICD-9 or ICD-10) and Alzheimer disease was mainly diagnosed according to clinical criteria (eg, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criteria). Effect estimates were calculated using the inverse-variance weighted method. The Mendelian randomization analysis showed nonsignificant association of genetically predicted AF with risk of Alzheimer disease (odds ratio=1.002, 95% CI: 0.996-1.009, P=0.47) using 93 single nucleotide polymorphisms as the instruments. Mendelian randomization-Egger indicated no evidence of genetic pleiotropy (intercept=0.0002, 95% CI: -0.001 to 0.001, P=0.70). Conclusions This Mendelian randomization analysis found no evidence to support causal association between AF and Alzheimer disease.
| S-EPMC7033843 | biostudies-literature
Project description:BackgroundPrevious studies have found atrial fibrillation (AF) is associated with valvular heart disease (VHD). However, whether there is a causal relationship between these two diseases or it is just a result of bias caused by confounding factors is uncertain. This study aims to examine the potential causal association between AF and VHD by using Mendelian randomization.MethodsIn order to examine the causal relationship between AF and VHD, we performed a two-sample Mendelian randomization study by collecting exposure and outcome data from genome-wide association study (GWAS) datasets. We utilized data from FinnGen project (FinnGen, 11,258 cases for VHD including rheumatic fever, 3,108 cases for non-rheumatic VHD, and 75,137 cases for participants) and European Bio-informatics Institute database (EBI, 55,114 cases for AF and 482,295 cases for participants). Inverse-variance weighted (IVW), MR-Egger, and weighted median approaches were performed to estimate the causal effect.ResultsThe Mendelian randomization analysis indicated that AF increased the risk of VHD by all three MR methods [For VHD including rheumatic fever: IVW, odds ratio (OR) = 1.255; 95% confidence interval (CI), 1.191~1.322; p = 1.23 × 10-17; Weighted median, OR = 1.305, 95% CI, 1.216~1.400, p = 1.57 × 10-13; MR-Egger, OR = 1.250, 95% CI, 1.137~1.375, p = 1.69 × 10-5; For non-rheumatic VHD: IVW, OR = 1.267; 95% CI, 1.169~1.372; p = 6.73 × 10-9; Weighted median, OR = 1.400; 95% CI, 1.232~1.591; p = 2.40 × 10-7; MR-Egger, OR = 1.308; 95% CI, 1.131~1.513; p = 5.34 × 10-4]. After the one outlier SNP was removed by heterogeneity test, the results remained the same. No horizontal pleiotropic effects were observed between AF and VHD.ConclusionsOur study provides strong evidence of a causal relationship between AF and VHD. Early intervention for AF patients may reduce the risk of developing into VHD.
| S-EPMC8996053 | biostudies-literature
Project description:BackgroundThe causal role of interleukins (ILs) for cardiovascular disease has not been fully elucidated. We conducted a Mendelian randomization study to investigate the associations of circulating ILs with coronary artery disease (CAD), atrial fibrillation (AF), and ischemic stroke.Methods and resultsSingle-nucleotide polymorphisms associated with IL-1β, IL-1 receptor antagonist (IL-1ra), IL-2 receptor subunit alpha, IL-6, IL-16, IL-17 and IL-18 were identified from genome-wide association studies. Summary-level data of the outcomes were obtained from three large consortia. Genetic predisposition to higher IL-1ra levels were significantly associated with CAD. The odds ratio was 1.36 (95% confidence interval (CI), 1.14-1.63; P = 5.37 × 10-4) per one standard deviation increase in IL-1ra levels. Genetically higher IL-6 levels, predicted by a variant in the IL6R gene and corresponding to reduced IL-6 bio-function, were significantly inversely associated with CAD and AF. The odds ratios per one standard deviation increase in IL-6 levels were 0.64 (95%CI, 0.54-0.76; P = 2.22 × 10-7) for CAD and 0.70 (95%CI, 0.62-0.80; P = 1.34 × 10-7) for AF. There was a suggestive positive association of IL-1ra with cardioembolic stroke and suggestive inverse associations of IL-6 with any ischemic stroke, cardioembolic stroke, and small vessel stroke, and of IL-16 with CAD. The other ILs were not associated with any outcome.ConclusionsThese results strengthen the evidence that IL-6 inhibition may offer a therapeutic approach for prevention of CAD, AF, and ischemic stroke. In contrast, IL-1 inhibition through raised IL-1ra levels may confer increased risk of CAD and cardioembolic stroke. The role of IL-16 for CAD warrants further investigation.
| S-EPMC7611848 | biostudies-literature
Project description:BackgroundAtrial fibrillation is a common cardiovascular disorder, characterized by irregular electrical activity in the upper chambers of the heart. Both chronic cardiometabolic risk factors and genetics have been shown to contribute to the development of atrial fibrillation. Birthweight has also been associated with risk of atrial fibrillation.MethodsIn the current study, we utilized a genetic approach to study the effect of birthweight on atrial fibrillation. We used 2-sample Mendelian randomization to consider the impact of birthweight on incident atrial fibrillation using summary data from the Early Growth Genetics Consortium GWAS of birthweight and a large biobank-based GWAS of atrial fibrillation.ResultsUsing the framework of 2-sample Mendelian randomization, we found that a 1-SD genetic elevation of birthweight was associated with increased risk of atrial fibrillation (odds ratio, 1.27 [95% CI, 1.14-1.41]; P=1×10-5) with sensitivity analyses demonstrating robustness of this result.ConclusionsOur findings clarify the directionality of the relationship between birthweight and atrial fibrillation, supporting the growing body of evidence that intrauterine growth has a lifelong impact on cardiovascular health.
| S-EPMC7299774 | biostudies-literature
Project description:ContextAtrial fibrillation (AF), cardiac arrhythmias, and related risk factors are common in patients with Cushing's syndrome, or clinical chronic hypercortisolism. While hypercortisolism may be associated with AF, this association has not yet been ascertained causally.ObjectiveTo determine whether plasma cortisol is causally associated with AF using a 2-sample Mendelian randomization (MR) design.MethodsThree genetic variants in the SERPINA1/SERPINA6 locus and functionally associated with plasma cortisol were identified in the CORtisol NETwork consortium (12 597 participants). Summary-level genome-wide association study (GWAS) data for the associations between the cortisol-associated variants and AF were obtained from a GWAS meta-analysis of 6 studies (60 620 AF cases and 970 216 noncases) and the FinnGen consortium (17 325 AF cases and 97 214 noncases). The fixed-effects inverse-variance weighted approach accounting for genetic correlations between variants was used for analysis. Multivariable MR analyses were conducted to assess potential mediating effects of systolic blood pressure (SBP) and waist circumference (WC). Summary-level GWAS data for SBP and WC were obtained respectively from the International Consortium of Blood Pressure (757 601 participants) and the Genetic Investigation of ANthropometric Traits consortium (232 101 participants).ResultsOne standard deviation increase in genetically predicted plasma cortisol was associated with greater risk of AF (odds ratio [OR] 1.20, 95% CI 1.06-1.35). The association attenuated when adjusting for genetically predicted SBP and WC (OR 0.99, 95% CI 0.72-1.38).ConclusionEvidence derived from the MR study suggests a positive association between plasma cortisol and risk of AF, likely mediated through SBP and WC.
| S-EPMC8208666 | biostudies-literature
Project description:Background and objectivesThe association between bilirubin and atrial fibrillation (AF) has been evaluated previously in observational studies but with contradictory results. This study evaluated the causal association between serum bilirubin level and AF using Mendelian randomization (MR) analysis.MethodsThis cross-sectional study includes 8,977 participants from the Dong-gu Study. In the observational analysis, multivariate logistic regression was performed to evaluate the association between bilirubin and prevalent AF. To evaluate the causal association between bilirubin and AF, MR analysis was conducted by using the UGT1A1 rs11891311 and rs4148323 polymorphisms as instrumental variables.ResultsElevated serum bilirubin levels were associated with an increased risk for AF in observational analysis (total bilirubin: odds ratio [OR], 1.31; 95% confidence interval [95% CI], 1.15-1.48 per 1 standard deviation [SD]; direct bilirubin: OR, 1.31; 95% CI, 1.18-1.46 per 1 SD), whereas the genetically predicted serum bilirubin levels in MR analysis did not show this association (total bilirubin: OR, 1.02; 95% CI, 0.67-1.53 per 1 SD; direct bilirubin: OR, 1.03; 95% CI, 0.61-1.73 per 1 SD).ConclusionsGenetically predicted bilirubin levels were not associated with prevalent AF. Thus, the observational association between serum bilirubin levels and AF may be non-causal and affected by reverse causality or unmeasured confounding.
| S-EPMC10406528 | biostudies-literature
Project description:Introduction: Hypertension (HT) and atrial fibrillation (AF) often coexist. However, the causality between these two conditions remains to be determined. Methods: We used individual participant data from the Atherosclerosis Risk in Communities (ARIC) prospective cohort with 9,474 participants. HT was ascertained at visit 1 (1987-1989), and incident AF was identified by ECGs conducted during study examinations at each visit, hospital discharge codes, and death certificates. We used the Kaplan-Meier estimate to compute the cumulative incidence of AF by the HT subgroup. Then we used Cox hazard regression model to assess the association between HT and incident AF. The causality between genetically determined HT and AF was analyzed by the two-sample Mendelian randomization (MR) based on publicly summarized genome-wide association studies (GWASs) data. Results: A total of 1,414 cases (14.9%) of AF were identified during the follow-up period (median 24.1 years). After adjusting for all covariates, the hazard ratio between the participants with HT and incident AF was 1.50 [95% confidence interval (CI) 1.29-1.73]. In the HT → AF MR analysis, we detected a causal correlation between HT and AF (OR: 1.90, 95% CI 1.18-3.04, P = 0.01) with no evidence of heterogeneity from single-nucleotide polymorphisms. Besides, the genetically determined SBP and DBP (10 mmHg) were consistently associated with a higher risk of AF. Conclusions: In the ARIC study, the incident AF increased by 50% in patients with HT. In the MR analysis, our results supported causal inference between HT and AF.
| S-EPMC8021766 | biostudies-literature