Mendelian Randomization to Evaluate the Causal Effect of Serum Bilirubin on Atrial Fibrillation.
Ontology highlight
ABSTRACT:
SUBMITTER: Hisamatsu T
PROVIDER: S-EPMC10406531 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
Publications
Mendelian Randomization to Evaluate the Causal Effect of Serum Bilirubin on Atrial Fibrillation.
Korean circulation journal 20230510 7
Similar Datasets
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:ObjectivesPrevious research has predominantly focused on total bilirubin levels without clearly distinguishing between direct and indirect bilirubin. In this study, the differences between these forms were examined, and their potential causal relationships with ischemic stroke were investigated.MethodsTwo-sample multivariable Mendelian randomization (MVMR) analysis was employed, extracting summary data on bilirubin from the Korean Cancer Prevention Study-II (n=159,844) and the Korean Genome and Epidemiology Study (n=72,299). Data on ischemic stroke were obtained from BioBank Japan (n=201,800). Colocalization analysis was performed, focusing on the UGT1A1, SLCO1B1, and SLCO1B3 genes, which are the primary loci associated with serum bilirubin levels.ResultsCrude 2-sample Mendelian randomization analysis revealed a significant negative association between total bilirubin levels and ischemic stroke. However, in MVMR analyses, only indirect bilirubin demonstrated a significant negative association with ischemic stroke (odds ratio, 0.76; 95% confidence interval, 0.59 to 0.98). Colocalization analysis did not identify a shared causal variant between the 3 genetic loci related to indirect bilirubin and the risk of ischemic stroke.ConclusionsOur study establishes a causal association between higher genetically determined levels of serum indirect bilirubin and reduced risk of ischemic stroke in an Asian population. Future research should include more in-depth analysis of shared genetic variants between indirect bilirubin and ischemic stroke.
| S-EPMC11826012 | biostudies-literature
Project description:Background Obstructive sleep apnea (OSA) has shown to be associated with an increased risk of atrial fibrillation in observational studies. Whether this association reflect causal effect is still unclear. The aim of this study was to evaluate the causal effect of OSA on atrial fibrillation. Methods and Results We used a 2-sample Mendelian randomization (MR) method to evaluate the causal effect of OSA on atrial fibrillation. Summary data on genetic variant-OSA association were obtained from a recently published genome-wide association studies with up to 217 955 individuals and data on variant-atrial fibrillation association from another genome-wide association study with up to 1 030 836 individuals. Effect estimates were evaluated using inverse-variance weighted method. Other MR analyses, including penalized inverse-variance weighted, penalized robust inverse-variance weighted, MR-Egger, simple median, weighted median, weighted mode-based estimate and Mendelian Randomization Pleiotropy Residual Sum and Outlier methods were performed in sensitivity analyses. The MR analyses in both the fixed-effect and random-effect inverse-variance weighted models showed that genetically predicted OSA was associated with an increased risk of atrial fibrillation (odds ratio [OR], 1.21; 95% CI, 1.12-1.31, P<0.001; OR, 1.21; 95% CI, 1.11-1.32, P<0.001) using 5 single nucleotide polymorphisms as the instruments. MR-Egger indicated no evidence of genetic pleiotropy (intercept, -0.014; 95% CI, -0.033 to 0.005, P=0.14). Results were robust using other MR methods in sensitivity analyses. Conclusions This MR analysis found that genetically predicted OSA had causal effect on an increased risk of atrial fibrillation.
| S-EPMC9075405 | 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:BackgroundAtrial fibrillation (AF) is one of the most common persistent arrhythmias among adult cardiovascular diseases. It is important to identify potential risk factors for AF. Members of the insulin-like growth factor (IGF) family exert a variety of effects on various cell types in the context of the pathogenesis of cardiovascular diseases, and previous population-based studies indicate associations between IGF family members and AF. However, the causal effects of IGF family members in AF have not been evaluated.AimIn the current study two-sample Mendelian Randomization (MR) was used to assess genetic relationships between IGF family members and AF.MethodsMR was performed based on genome-wide association study (GWAS) datasets, and concentration levels of 14 IGF family members were retrieved. An initial MR analysis was conducted to identify single nucleotide polymorphisms potentially associated with IGF serum concentrations. A GWAS meta-analysis including 60620 AF cases and 970216 control participants of European ancestry was then conducted to identify AF causal effects. Two-sample MR packages were used to perform MR analysis in R. MR-Egger, weighted median (WM), and inverse variance weighted (IVW) methods were used.ResultsIn two-sample MR assessments there were lower levels of circulating IGF binding protein 3 in both WM [odds ratio (OR) 0.964, 95% confidence interval (CI) 0.940-0.960, P = 0.006] and IVW (OR 0.968, 95%CI: 0.947-0.987, P = 0.001) analyses. Higher serum levels of IGF2 receptor were associated with AF (OR 1.045, 95%CI: 1.016-1.076, P = 0.039). In reverse MR analysis conducted to investigate casual effects, elevated levels of circulating CYR61 were associated with AF (OR 1.060, 95%CI: 1.005-1.119, P = 0.031).ConclusionThe results of the present study provide novel insights into the pathogenesis of AF, and the implications of serum IGF family member concentrations when assessing the risk of AF. The study generated evidence on the potential roles of developmental pathological effects in the pathogenesis of AF. Further observational and experimental studies are critically needed.
| S-EPMC10768518 | biostudies-literature
Project description:BackgroundObservational studies indicate that serum urate level is associated with atrial fibrillation (AF). However, whether this association is causal remains controversial, due to confounding factors and reverse causality. We aim to evaluate the causal relationship of genetically predicted serum urate level with AF.MethodsA bidirectional Mendelian randomization (MR) study was performed. Instrumental variables were obtained from the Global Urate Genetics Consortium (110347 individuals). We obtained summary statistics of AF from two genome-wide association studies (GWAS) data sets for AF. Inverse-variance-weighted method was applied to obtain MR estimates and other statistical methods were conducted in the sensitivity analyses. The reverse MR analysis was performed to evaluate the effect of AF on serum urate levels.ResultsGenetically determined serum urate level was not associated with AF in two studies (OR, 1.03; 95% CI, 0.95-1.11; p = 0.47); (OR, 1.06; 95% CI, 0.99-1.12; p = 0.09). The main results kept robust in the most sensitivity analyses. Multivariable MR analyses suggested that the association pattern did not change, after adjusting for body mass index (BMI), HbA1c: hemoglobin A1c (HbA1c), hypertension, low-density lipoprotein cholesterol (LDL-C) and coronary heart disease. No causal effect of AF on serum urate levels was found in two studies (OR, 1.02; 95% CI, 0.98-1.05; p = 0.30); (OR, 1.00; 95% CI, 0.98-1.03; p = 0.95).ConclusionsOur MR study supports no bidirectional causal effect of serum urate levels and AF. This implies that treatments aimed at lowering uric acid may not reduce the risk of AF.
| S-EPMC11772717 | biostudies-literature
Project description:Background and objectivesPrevious observational studies presented a positive association between alcohol and atrial fibrillation (AF). However, previous studies using genetic polymorphisms on the causal relationship between alcohol consumption and AF have reported conflicting results. This study aimed to evaluate the causality between alcohol consumption and AF using the aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which is the genetic variant with the most potent effect on drinking behavior.MethodsA total of 8,964 participants from the Dong-gu Study were included in the present study. The causal association between alcohol consumption and AF was evaluated through a Mendelian randomization (MR) analysis using the ALDH2 rs671 polymorphism as an instrumental variable.ResultsNo significant relationship between alcohol consumption and AF was found in the observational analysis. However, the genetic analysis using the ALDH2 polymorphism showed a significant association in men. In the MR analysis, genetically predicted daily alcohol consumption was positively related to AF.ConclusionsMR analysis revealed a significant association between the amount of alcohol consumption and AF, which suggests that the association may be causal.
| S-EPMC8907994 | biostudies-literature
Project description:AimsSeveral observational studies indicated that atrial fibrillation might aggravate other cardiovascular diseases apart from ischaemic stroke. However, it remains to be determined whether these associations reveal independent causation. Using Mendelian randomization (MR), we systematically investigated how genetically predicted atrial fibrillation affected other cardiovascular diseases and cardiac death.Methods and resultsSummary-level data for atrial fibrillation and other cardiovascular diseases were obtained from public genome-wide association study data. The random inverse-variance weighted method was treated as the primary analysis. Sensitivity analyses (including weighted median, MR-Egger, and multivariable MR methods) were also performed. Atrial fibrillation was significantly associated with higher risks of heart failure [odds ratio (OR): 1.24; 95% confidence interval (CI): 1.19-1.28; P < 0.001], ischaemic stroke (OR: 1.21; 95% CI: 1.17-1.25; P < 0.001), transient ischaemic attack (OR: 1.10; 95% CI: 1.05-1.15; P < 0.001), peripheral artery diseases (OR: 1.09; 95% CI: 1.03-1.15; P = 0.002), cardiac death (OR: 1.08; 95% CI: 1.02-1.15; P = 0.008), and hypertension (OR: 1.06; 95% CI: 1.01-1.11; P = 0.010), without effects on coronary heart disease or pulmonary embolism. Associations for heart failure and ischaemic stroke remained robust to the sensitivity analyses. MR-Egger method (P > 0.05) and funnel plot yielded no indication of directional pleiotropy. The leave-one-out analysis suggested that the causal associations were not driven by individual single nucleotide polymorphism.ConclusionsThis comprehensive MR analysis verified the causal associations between atrial fibrillation and high risks of heart failure, ischaemic stroke, transient ischaemic attack, peripheral artery diseases, cardiac death, and hypertension. Interventions to reduce cardiovascular diseases beyond ischaemic stroke are warranted in patients with atrial fibrillation.
| S-EPMC9871698 | biostudies-literature
Project description:Chronic kidney disease (CKD) and atrial fibrillation are both major burdens on the health care system worldwide. Several observational studies have reported clinical associations between CKD and atrial fibrillation; however, causal relationships between these conditions remain to be elucidated due to possible bias by confounders and reverse causations. Here, we conducted bidirectional two-sample Mendelian randomization analyses using publicly available summary statistics of genome-wide association studies (the CKDGen consortium and the UK Biobank) to investigate causal associations between CKD and atrial fibrillation/flutter in the European population. Our study suggested a causal effect of the risk of atrial fibrillation/flutter on the decrease in serum creatinine-based estimated glomerular filtration rate (eGFR) and revealed a causal effect of the risk of atrial fibrillation/flutter on the risk of CKD (odds ratio, 9.39 per doubling odds ratio of atrial fibrillation/flutter; 95% coefficient interval, 2.39-37.0; P = 0.001), while the causal effect of the decrease in eGFR on the risk of atrial fibrillation/flutter was unlikely. However, careful interpretation and further studies are warranted, as the underlying mechanisms remain unknown. Further, our sample size was relatively small and selection bias was possible.
| S-EPMC8668124 | biostudies-literature
Project description:BackgroundObservational studies about the association between serum total bilirubin and cholelithiasis are inconsistent. Hence, it is essential to reevaluate the association between serum total bilirubin and cholelithiasis and to verify whether such association is causal or not.MethodsWe selected single-nucleotide polymorphisms (SNPs) that are strongly associated with exposure as instrumental variable and conducted a bidirectional two-sample Mendelian randomization (MR) study to explore the causal association between serum total bilirubin and cholelithiasis. We implemented the inverse-variance weighted approach as a primary analysis to combine the Wald ratio estimates. Four additional analyses, namely, MR-Egger regression, weighted median, weighted mode, and MR-pleiotropy residual sum and outlier (PRESSO), were utilized to investigate the causal association and the influence of potential pleiotropy.ResultsA total of 116 SNPs were selected as valid instrumental variables to estimate the causal association of serum total bilirubin on cholelithiasis, and causal association between genetically determined serum total bilirubin and cholelithiasis was demonstrated [beta = 0.10; 95% confident interval (CI), 0.07 to 0.14; p < 0.001]. Likewise, the other methods, namely, the weighted median (beta = 0.12; 95% CI, 0.08 to 0.15; p < 0.001), MR-Egger (beta = 0.11; 95% CI, 0.08 to 0.15; p < 0.001), weighted mode (beta = 0.11; 95% CI, 0.08 to 0.15; p < 0.001), and MR-PRESSO approaches, further confirmed that this result (p = 0.054) indicates similar results. In addition, seven SNPs were selected as instrumental variable to estimate causal association of cholelithiasis on serum total bilirubin, and the result supported the causal effect of cholelithiasis to serum total bilirubin (beta = 0.12; 95% CI, 0.09 to 0.15; p < 0.001). At the same time, the other methods, namely, the weighted median (beta = 0.10; 95% CI, 0.06 to 0.13; p < 0.001), MR-Egger (beta = 0.12; 95% CI, 0.07 to 0.18; p = 0.007), weighted mode (beta = 0.09; 95% CI, 0.03 to 0.14, p = 0.019), and MR-PRESSO methods, further confirmed this result (p < 0.001).ConclusionOur MR study revealed that the serum total bilirubin was causally associated with the risk of cholelithiasis, and the genetic predisposition to cholelithiasis was causally associated with the increased serum total bilirubin levels.
| S-EPMC10352914 | biostudies-literature