Key result
Genetic liability to AF is linked to ~2-fold higher risk of cardioembolic stroke.
Why the study?
Atrial fibrillation contributes to stroke, but the extent to which it mediates causal associations between a wide range of risk factors and stroke was not quantified.
Does atrial fibrillation mediate the causal associations between various risk factors and stroke in individuals of European ancestry?
Observational
Mendelian randomization
Yes
Does atrial fibrillation mediate the causal associations between various risk factors and stroke in individuals of European ancestry?
Odds Ratio: 2.02 (95% CI 1.9–2.15)
p-value: p=1.40× 10 -111
Atrial fibrillation strongly mediates the causal effects of various cardiovascular risk factors on cardioembolic stroke, but not on other stroke subtypes, emphasizing the need for targeted AF management to prevent cardioembolic events.
AF largely mediates risk factor effects on cardioembolic stroke; hypothesis-generating for targeted prevention, requiring prospective validation before practice change.
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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Qin et al. (2023) conducted an observational in Stroke and its subtypes. Genetically predicted atrial fibrillation vs. Lack of genetically predicted atrial fibrillation was evaluated on Cardioembolic stroke (CES) (OR 2.02, 95% CI 1.90 to 2.15, p=1.40× 10 -111). Genetic liability to atrial fibrillation was associated with a significantly increased risk of cardioembolic stroke (OR 2.02) and largely mediated the causal associations between multiple risk factors and cardioembolic stroke.
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