Thyroid function affects the risk of stroke via atrial fibrillation: a Mendelian Randomization study.

Abstract

CONTEXT: Observational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not. OBJECTIVE: To test whether genetically determined variation in normal-range thyroid function is causally associated with the risk of stroke and Coronary Artery Disease (CAD), and investigate via which pathways these relations may be mediated. DESIGN: Setting and ParticipantsMendelian Randomization (MR) analyses for stroke and CAD using genetic instruments associated with normal-range TSH and FT4 levels or Hashimoto's disease and Graves' disease. The potential mediating role of known stroke and CAD risk factors was examined. Publically available summary statistics data were used. MAIN OUTCOME MEASURES: Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels. RESULTS: A one SD increase in TSH was associated with a 5% decrease in the risk of stroke (OR=0.95, 95% CI= 0.91 to 0.99, p=0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation (AF). MR analyses did not show a causal association between normal-range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto's Disease and a 7% increased risk of CAD (OR=1.07, 95% CI= 1.01 to 1.13, p=0.026), which was mainly mediated via body mass index. CONCLUSION: These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke and CAD. We identify variation in normal-range thyroid function and Hashimoto's Disease as risk factors for stroke and CAD, respectively.