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

Abstract

49Background 50 Several observational studies suggest that variations in thyroid function, even within the normal 51 range, are a risk factor for cardiovascular diseases, but it remains to be determined if these 52 associations are causal or not. This study investigates whether the relationship between variation 53 in normal range thyroid function, as well as hypothyroidism and hyperthyroidism, and the risk of 54 stroke and Coronary Artery Disease (CAD) are causal and via which pathways these relations are 55 mediated. 56 Methods and Findings 57We performed Mendelian Randomization (MR) analyses for stroke and CAD using genetic 58 instruments associated with TSH and FT4 levels respectively within either the normal range, 59 hypothyroidism or hyperthyroidism. In detected associations, the potential mediatory role of 60 known stroke and CAD risk factors was also examined. A one standard deviation increase in TSH 61 was associated with a 5% decrease in the risk of stroke (OR=0.95, 95% CI= 0.91 to 0.99). 62Multivariable MR analyses indicated that this effect is mediated through atrial fibrillation (AF). 63Hashimoto's Disease (HD) was associated with a 7% increased risk of CAD (OR=1.07, 95% CI= 64 1.01 to 1.13). The effect of Hashimoto's Disease (HD) on CAD risk appears to be mediated via 65 body mass index (BMI). 66 Conclusions 67These results provide important new insights into the causal relationships and mediating pathways 68 between thyroid function, stroke and CAD. Specifically, we identify normal range TSH levels and 69 HD as potential modifiable risk factors for stroke and CAD, respectively. 70 71