Causal Effect of Obstructive Sleep Apnea on Atrial Fibrillation: A Mendelian Randomization Study

Abstract

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.

Sleep Disordered Breathing, Obesity and Atrial Fibrillation: A Mendelian Randomisation Study

“…An association between OSA and increased risk of AF in community and sleep clinic cohorts has been reported in observational studies [ 4 , 5 , 6 ] and observational meta-analysis reported reduced AF recurrence with CPAP therapy [ 7 ]. Similarly, a recent MR study reported a Mendelian randomisation association between genetically proxied OSA and AF, though only five SNPs were instrumented in this analysis, with two associated with BMI or whole-body, fat-free mass at the genome-wide significance level [ 20 ]. Our study builds on these data by including almost six-fold more SNPs significantly correlated with sleep apnoea traits, in addition to performing multivariable MR to control for the well-characterised, powerful pleiotropic effects of BMI on the relationship between SDB and AF.…”

“…In this way, MR can potentially overcome limitations associated with classical observational epidemiology, namely confounding and reverse causality [ 19 ], and may permit delineation of complex pathways relating SDB, BMI and AF. A recent univariable MR study reported a causal association between five single-nucleotide polymorphisms (SNPs) associated with OSA and AF [ 20 ]. However, some of the employed OSA instruments were also associated with BMI or whole-body, fat-free mass at the genome-wide significance level, raising the question of whether this relationship was partially mediated via obesity.…”

Assessment of the Causal Effects of Obstructive Sleep Apnea on Atrial Fibrillation: A Mendelian Randomization Study

“…With an instrumental variable analysis and a huge sample size, the MR approach can be used to study a cause-and-effect relationship without interferences of bias and confounding that are hard to circumvent in observational design, thus it is more appropriate for our exposure and outcome set. Chen (39) did an MR analysis to investigate the association between OSA and AF. They reported that OSA was related to an increased risk of AF.…”

Obesity as a risk factor for cardiac arrhythmias

“…One Mendelian randomisation study showed that the genetic propensity for obstructive sleep apnoea also increased AF risk (odds ratio 1.21 (95% confidence interval 1.12 to 1.31)). 66 However, this analysis was based on only five single nucleotide polymorphisms, of which two were also associated with body mass index or fat-free mass at the genome wide significance level, suggesting this link could be mediated by obesity. Indeed, another Mendelian randomisation study including almost sixfold single nucleotide polymorphisms showed that although obstructive sleep apnoea was associated with AF in univariable analysis (odds ratio 2.09 (95% confidence interval 1.10 to 3.98)), this finding became non-significant after adjustment for body mass index (0.68 (0.42 to 1.10)).…”