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Mendelian Randomization analyses reveal a causal effect of thyroid function on stroke via atrial fibrillation

By Eirini Marouli, Aleksander Kus, M. Fabiola Del Greco, Layal Chaker, Robin Peeters, Alexander Teumer, Panos Deloukas, Marco Medici

Posted 30 Jul 2019
bioRxiv DOI: 10.1101/718429

Background: Several observational studies suggest that variations in thyroid function, even within the normal range, are a risk factor for cardiovascular diseases, but it remains to be determined if these associations are causal or not. This study investigates whether the relationship between variation in normal range thyroid function, as well as hypothyroidism and hyperthyroidism, and the risk of stroke and Coronary Artery Disease (CAD) are causal and via which pathways these relations are mediated. Methods and Findings: We performed Mendelian Randomization (MR) analyses for stroke and CAD using genetic instruments associated with TSH and FT4 levels respectively within either the normal range, hypothyroidism or hyperthyroidism. In detected associations, the potential mediatory role of known stroke and CAD risk factors was also examined. A one standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (OR=0.95, 95% CI= 0.91 to 0.99). Multivariable MR analyses indicated that this effect is mediated through atrial fibrillation (AF). Hashimoto's Disease (HD) was associated with a 7% increased risk of CAD (OR=1.07, 95% CI= 1.01 to 1.13). The effect of Hashimoto's Disease (HD) on CAD risk appears to be mediated via body mass index (BMI). Conclusions: These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke and CAD. Specifically, we identify normal range TSH levels and HD as potential modifiable risk factors for stroke and CAD, respectively.

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