Thyroid Function Affects the Risk of Stroke via Atrial Fibrillation: A Mendelian Randomization Study

• Published in: The journal of clinical endocrinology and metabolism Vol. 105; no. 8; pp. 2634 - 2641
• Main Authors: Marouli, Eirini, Kus, Aleksander, Del Greco M, Fabiola, Chaker, Layal, Peeters, Robin, Teumer, Alexander, Deloukas, Panos, Medici, Marco
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-08-2020
• Subjects: Adult; Atrial fibrillation; Atrial Fibrillation - epidemiology; Atrial Fibrillation - genetics; Body Mass Index; Clinical s; Coronary Artery Disease - epidemiology; Coronary Artery Disease - genetics; Coronary heart disease; Datasets as Topic; Female; Genetic aspects; Genetics; Graves Disease - blood; Graves Disease - complications; Graves Disease - diagnosis; Graves Disease - genetics; Hashimoto Disease - blood; Hashimoto Disease - complications; Hashimoto Disease - diagnosis; Hashimoto Disease - genetics; Humans; Male; Mediation; Medical research; Medicine, Experimental; Mendelian Randomization Analysis; Middle Aged; Polymorphism, Single Nucleotide; Reference Values; Risk Factors; Stroke (Disease); Stroke - epidemiology; Stroke - genetics; Thyroid diseases; Thyroid Function Tests; Thyroid gland; Thyroid Gland - physiopathology; Thyrotropin; Thyrotropin - blood; Thyroxine; Thyroxine - blood; Type 2 diabetes; United Kingdom; Netherlands; coronary artery disease; TSH; thyroid function; Mendelian randomization; mediation; stroke
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgaa239

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 Participants
Mendelian randomization analyses for stroke and CAD using genetic instruments associated with normal range thyrotropin (TSH) and free thyroxine levels or Hashimoto’s thyroiditis and Graves’ disease. The potential mediating role of known stroke and CAD risk factors was examined. Publicly available summary statistics data were used.
Main Outcome Measures
Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels.
Results
A 1 standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; P = 0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation. MR analyses did not show a causal association between normal range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto’s thyroiditis and a 7% increased risk of CAD (OR, 1.07; 95% CI, 1.01-1.13; 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 thyroiditis as risk factors for stroke and CAD, respectively.