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The mediating role of atrial fibrillation in causal associations between risk factors and stroke: a Mendelian randomization study
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Shanmei Qin, Mengmeng Wang, Dipender Gill, Zhizhong Zhang, Xinfeng Liu
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Epidemiol Health. 2024;46:e2024005. Published online December 6, 2023
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DOI: https://doi.org/10.4178/epih.e2024005
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 Abstract
Summary
 PDF Supplementary Material
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Abstract
OBJECTIVES
Atrial fibrillation (AF) contributes to stroke development and progression. We aimed to quantify the mediating role of AF in the causal associations between a wide range of risk factors and stroke via a Mendelian randomization (MR) framework.
METHODS We assessed the associations of 108 traits with stroke and its subtypes in a 2-sample univariable MR approach, then conducted a bidirectional MR analysis between these 108 traits and AF to evaluate the presence and direction of their causal associations. Finally, to further investigate the extent to which AF mediated the effects of eligible traits on stroke, we applied multivariable and 2-step MR techniques in a mediation analysis where outcomes were restricted to stroke types causally affected by AF (any stroke [AS], any ischemic stroke [AIS], and cardioembolic stroke [CES]).
RESULTS Among 108 traits, 42 were putatively causal for at least 1 stroke type; of these 42 traits, 20 that had no bidirectional relationship with AF were retained. Finally, 33 associations of 15 eligible traits were examined in the mediation analysis. The mediation analyses for AS, AIS, and CES each included 11 eligible traits. After AF adjustment, the direct effects of all traits on CES were attenuated to null (all p>0.05), while the associations with AS and AIS persisted for most traits (AF-mediated proportion: from 6.6% [95% confidence interval, 2.7 to 0.6] to 52.0% [95% confidence interval, 39.8 to 64.3]).
CONCLUSIONS The causal associations between all eligible traits and CES were largely mediated through AF, while most traits affected AS and AIS independently of AF.
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Summary
Key Message
Previous studies have not systematically detected and quantified the mediating role of AF in causal associations between a wide range of risk factors and stroke types. This study, using several MR approaches, found that the causal associations between risk factors and stroke, and the role of AF in mediating these associations, varied across stroke types. Although AF largely mediated the trait-CES associations, most traits affected AS and AIS independently of AF, highlighting the need for accurate disease classification in clinical practice and trials.
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