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

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

doi:10.3389/fgene.2021.619536

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

Front Genet. 2021 May 26:12:619536. doi: 10.3389/fgene.2021.619536. eCollection 2021.

Authors

Songzan Chen¹, Fangkun Yang², Tian Xu¹, Yao Wang¹, Kaijie Zhang¹, Guosheng Fu¹, Wenbin Zhang¹

Affiliations

¹ Key Laboratory of Biotherapy of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² Department of Cardiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

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.

Keywords: Mendelian randomization; atrial fibrillation; causal association; genome-wide association study; homocysteine.