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

Songzan Chen,Guosheng Fu,Wenbin Zhang,Fangkun Yang,Tian Xu,Kaijie Zhang,Yao Wang

doi:10.3389/fgene.2021.619536

Abstract

BackgroundAlthough 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.MethodsA 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.ResultsIn 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.ConclusionsThis two-sample MR analysis found no evidence to support causal association of Hcy with AF.

Highlights

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered clinically (Lip et al, 2012; Liu et al, 2018), and millions of individuals are expected to develop AF in the decades (Violi et al, 2016)
Background: 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 total, nine single nucleotide polymorphisms (SNPs) were identified as valid instrumental variables in our two-sample Mendelian randomization (MR) analysis

Summary

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered clinically (Lip et al, 2012; Liu et al, 2018), and millions of individuals are expected to develop AF in the decades (Violi et al, 2016). Patients with AF are at an increased risk of developing serious complications, including stroke, heart failure, dementia, and an early mortality (Magnani et al, 2011). As a well-known marker for pro-oxidation and proinflammation, elevated levels of homocysteine (Hcy) are considered as a risk factor/biomarker/predictor for developing cardiovascular disease (CVD) (Ganguly and Alam, 2015). Only several studies have addressed the association between Hcy and AF risk (Schnabel et al, 2010). 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. We aimed to investigate the causal association of plasma Hcy levels with AF risk

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