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Thyroid Function Affects the Risk of Stroke via Atrial Fibrillation: A Mendelian Randomization Study
Eirini Marouli1,2, Aleksander Kus3,4,5, Fabiola Del Greco M6
1William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Insights
Genetically predicted normal thyroid function influences stroke risk, mediated by atrial fibrillation. Hashimoto's thyroiditis increases coronary artery disease risk, primarily through body mass index.
Area of Science:
- Cardiovascular epidemiology
- Endocrinology
- Genetic epidemiology
Background:
- Observational studies link normal range thyroid function variations to cardiovascular diseases.
- Causality and mediating pathways remain undetermined.
Purpose of the Study:
- To investigate causal associations between genetically determined normal range thyroid function and stroke/coronary artery disease (CAD) risk.
- To explore mediating pathways for these relationships.
Main Methods:
- Mendelian randomization analyses utilized genetic instruments for thyrotropin (TSH), free thyroxine (FT4), Hashimoto's thyroiditis, and Graves' disease.
- Examined mediation by known stroke and CAD risk factors using publicly available summary statistics.
Main Results:
- A 1-SD increase in TSH was associated with a 5% reduced stroke risk, primarily mediated by atrial fibrillation.
- No causal link was found between normal range thyroid function and CAD.
- Hashimoto's thyroiditis showed a causal relationship with a 7% increased CAD risk, mediated by body mass index.
Conclusions:
- Normal range thyroid function variations are identified as risk factors for stroke.
- Hashimoto's thyroiditis is a risk factor for CAD.
- Elucidates causal relationships and mediating pathways between thyroid function and cardiovascular diseases.
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.
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