Dataset Information

Appraising the Causal Association of Plasma Homocysteine Levels With Atrial Fibrillation Risk: A Two-Sample Mendelian Randomization Study.

ABSTRACT:

Background

Although several observational studies have suggested an association of elevated plasma homocysteine (Hcy) levels with increased risk of atrial fibrillation (AF), it remains unclear whether this association reflects causality. In this study, we aimed to investigate the causal association of plasma Hcy levels with AF risk.

Methods

A two-sample Mendelian randomization (MR) study was designed to investigate the causal association of Hcy with AF. Summary data on association of single nucleotide polymorphisms (SNPs) with Hcy were extracted from the hitherto largest genome-wide association study (GWAS) with up to 44,147 individuals, and statistics data on association of SNPs with AF were obtained from another recently published GWAS with up to 1,030,836 individuals. SNPs were selected at a genome-wide significance threshold (p < 5 × 10^-8). Fixed-effect inverse variance weighting (IVW) method was used to calculate the causal estimate. Other statistical methods and leave-one-out analysis were applied in the follow-up sensitivity analyses. MR-Egger intercept test was conducted to detect the potential directional pleiotropy.

Results

In total, nine SNPs were identified as valid instrumental variables in our two-sample MR analysis. Fixed-effect IVW analysis indicated no evidence of causal association of genetically predicted Hcy with AF. The odds ratio (OR) and 95% confidence interval (CI) of AF per standard deviation (SD) increase in Hcy were 1.077 (0.993, 1.168), p = 0.075. Similar results were observed in the sensitivity analyses. MR-Egger intercept test suggested no evidence of potential horizonal pleiotropy.

Conclusions

This two-sample MR analysis found no evidence to support causal association of Hcy with AF.

SUBMITTER: Chen S

PROVIDER: S-EPMC8189424 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background: Observational studies have identified impaired lung function accessed by forced expiratory volume in one second (FEV1), forced vital capacity (FVC) or the ratio of FEV1 over FVC (FEV1/FVC) as an independent risk factor for atrial fibrillation (AF). However, the result may be affected by confounders or reverse causality. Methods: We performed univariable MR (uvMR), multivariable MR (mvMR) and bidirectional two-sample MR to jointly estimate the causality of lung function with AF. Apart from the inverse variance weighted (IVW) approach as the main MR analysis, three complementary sensitive analyses approaches including MR-Egger regression, weighted median (WM) MR and Pleiotropy Residual Sum and Outlier (MR-PRESSO) in uvMR as well as mvMR-Egger and mvMR-PRESSO in mvMR were applied to control for pleiotropy. Linkage disequilibrium score (LDSC) regression was applied to estimate genetic correlation between lung function and AF. Results: All forward and reverse uvMR analyses consistently suggested absent causal relations between lung function and AF risk [forward IVW: odds ratio (OR)FEV1 = 1.031, 95% CI = 0.909-1.169, P = 0.630; ORFVC = 1.002, 95% CI = 0.834-1.204, P = 0.982; ORFEV1/FVC = 1.076, 95% CI = 0.966-1.199, P = 0.182; reverse IVW: ORFEV1 = 0.986, 95% CI = 0.966-1.007, P = 0.187; ORFVC = 0.985, 95% CI = 0.965-1.006, P = 0.158; ORFEV1/FVC = 0.994, 95% CI = 0.973-1.015, P = 0.545]. The forward MR-Egger showed that each standard deviation (SD) increase in FEV1/FVC was related to a higher AF risk (OR = 1.502, 95% CI = 1.178-1.915, P = 0.006) without heterogeneity (Q_pval = 0.064), but pleiotropy effect exist (intercept = -0.017, P = 0.012). However, this significant effect disappeared after adjustment of FEV1 and FVC (OR = 1.523, 95% CI = 0.445-5.217, P = 0.503) in mvMR. No evidence was found for independent causal effects of FEV1 and FVC on AF in mvMR analysis by using mvIVW method (ORFEV1 = 0.501, 95% CI = 0.056-4.457, P = 0.496; ORFVC = 1.969, 95% CI = 0.288-13.474, P = 0.490). Notably, the association between lung function and AF were replicated using the FinnGen cohort data. Conclusions: Our findings reported no coheritability between lung function and AF, and failed to find substantial causal relation between decreased lung function and risk of AF. However, lung function and AF were both associated with inflammation, which may be potential pathway, warranting further study.

Project description:BACKGROUND:Observational studies have identified an association between body mass index (BMI) and incident atrial fibrillation (AF). Inferring causality from observational studies, however, is subject to residual confounding, reverse causation, and bias. The primary objective of this study was to evaluate the causal association between BMI and AF by using genetic predictors of BMI. METHODS:We identified 51?646 individuals of European ancestry without AF at baseline from 7 prospective population-based cohorts initiated between 1987 and 2002 in the United States, Iceland, and the Netherlands with incident AF ascertained between 1987 and 2012. Cohort-specific mean follow-up ranged from 7.4 to 19.2 years, over which period there was a total of 4178 cases of incident AF. We performed a Mendelian randomization with instrumental variable analysis to estimate a cohort-specific causal hazard ratio for the association between BMI and AF. Two genetic instruments for BMI were used: FTO genotype (rs1558902) and a BMI gene score comprising 39 single-nucleotide polymorphisms identified by genome-wide association studies to be associated with BMI. Cohort-specific estimates were combined by random-effects, inverse variance-weighted meta-analysis. RESULTS:In age- and sex-adjusted meta-analysis, both genetic instruments were significantly associated with BMI (FTO: 0.43 [95% confidence interval, 0.32-0.54] kg/m2 per A-allele, P<0.001; BMI gene score: 1.05 [95% confidence interval, 0.90-1.20] kg/m2 per 1-U increase, P<0.001) and incident AF (FTO, hazard ratio, 1.07 [1.02-1.11] per A-allele, P=0.004; BMI gene score, hazard ratio, 1.11 [1.05-1.18] per 1-U increase, P<0.001). Age- and sex-adjusted instrumental variable estimates for the causal association between BMI and incident AF were hazard ratio, 1.15 (1.04-1.26) per kg/m2, P=0.005 (FTO) and 1.11 (1.05-1.17) per kg/m2, P<0.001 (BMI gene score). Both of these estimates were consistent with the meta-analyzed estimate between observed BMI and AF (age- and sex-adjusted hazard ratio 1.05 [1.04-1.06] per kg/m2, P<0.001). Multivariable adjustment did not significantly change findings. CONCLUSIONS:Our data are consistent with a causal relationship between BMI and incident AF. These data support the possibility that public health initiatives targeting primordial prevention of obesity may reduce the incidence of AF.