Mild thyroid variation may predict stroke risk
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Minor variations in normal-range thyroid function may serve as a novel, modifiable risk factor for stroke, according to findings from a Mendelian randomization analysis published in The Journal of Clinical Endocrinology & Metabolism.
“Genetically determined higher thyroid-stimulating hormone levels within the normal range are associated with a lower risk for stroke, and this effect is mediated by a decreased risk for atrial fibrillation,” Eirini Marouli, PhD, a lecturer in computational biology at Barts and the London School of Medicine and Dentistry, Queen Mary University London, told Healio. “Hashimoto’s disease appears to be associated with an increased risk for coronary artery disease, which is mainly mediated via BMI.”
In primary analyses, Marouli and colleagues analyzed whether associations between variation in normal-range thyroid function, assessed via TSH and thyroxine levels, and the risk for stroke or coronary artery disease are causal. The researchers used 55 single nucleotide polymorphisms (SNPs) associated at a genome-wide level with TSH and 29 SNPs associated with free T4, as well as 20 genetic variants associated with Hashimoto’s thyroiditis and 49 genetic variants associated with Graves’ disease, using data from the UK Biobank. Two-sample Mendelian randomization analysis was performed using the inverse variance-weighted method. When Mendelian randomization showed a causal relationship between thyroid function and CAD or stroke, researchers used multivariable Mendelian randomization analyses to evaluate the role of known risk factors for stroke or CAD.
Researchers found that each standard deviation increase in TSH level was associated with a 5% decrease in risk for stroke (OR = 0.95; 95% CI, 0.91-0.99). In multivariable Mendelian randomization analyses, researchers found that the effect is mainly mediated via atrial fibrillation. Mendelian randomization analyses did not show a causal association between normal-range thyroid function and CAD.
“As no single method controls for all statistical properties that may affect Mendelian randomization estimates, we applied additional Mendelian randomization approaches that yielded similar results,” the researchers wrote. “Direction and effect sizes remained similar when restricting the analyses to Europeans only.”
Secondary analyses showed a causal relationship between Hashimoto’s thyroiditis and a 7% increased risk for CAD (OR = 1.07; 95% CI, 1.01-1.13), which was mainly mediated via BMI. There was no observed association between Hashimoto’s thyroiditis and stroke risk. There were no observed associations between Graves’ disease and stroke or CAD risk.
“Thyroid dysfunction affects 5% to 10% of the general population,” Marouli said. “Our findings have potential clinical implications, as they pave the way to consider future adjustment of thyroid function within the normal range in managing patients’ risk for stroke. Our results introduce minor variation in normal-range thyroid function as a novel, modifiable risk factor for stroke.”
As Healio previously reported, adults prescribed thyroid hormone therapy with low TSH levels had more atrial fibrillation and strokes compared with adults with higher TSH levels. In study data presented at the American Thyroid Association annual meeting in 2019, researchers found that incident atrial fibrillation was statistically significantly associated with lower vs. higher TSH level (OR = 0.97; 95% CI, 0.96-0.97), older vs. younger age (eg, aged 85 years: OR = 9.46; 95% CI, 8.98-9.96 compared with aged 18-49 years) and cardiovascular risk factors such as hypertension (OR = 1.73; 95% CI, 1.69-1.78). Similarly, stroke was significantly associated with lower TSH (OR = 0.98; 95% CI, 0.97-0.99) even when adjusting for other CV risk factors including history of prior atrial fibrillation.
The researchers wrote that the association between variation in normal-range thyroid function and stroke suggests that the use of classical population-based reference ranges might not be optimal for optimizing an individual’s disease risk.
“We aim to further disentangle the complex relationships between thyroid function including disease with different outcomes,” Marouli said. “Clinical trials could further confirm the necessity of future adjustment of thyroid function within the normal range.” – by Regina Schaffer
For more information:
Eirini Marouli, PhD, can be reached at the William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, Charterhouse Square, London, EC1M 6BQ; email: e.marouli@qmul.ac.uk; Twitter: @MarouliEirini.
Disclosures: The authors report no relevant financial disclosures.
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Maria Papaleontiou, MD
In this Mendelian randomization study, Marouli and colleagues showed that higher TSH levels within the normal range were associated with a lower risk for stroke, with one standard deviation increase in TSH associated with a 5% decrease in the risk for stroke, an effect mainly mediated by a decreased risk for atrial fibrillation. Moreover, in secondary analyses, the authors showed a causal relationship between Hashimoto’s disease and a 7% increased risk for coronary artery disease. However, no causal associations were found between free thyroxine and these outcomes.
In view of some prior studies demonstrating that free thyroxine levels may predict adverse events better than TSH concentrations, even within the euthyroid range, more research is needed to effectively understand these complex relationships. Findings from this study reinforce prior work suggesting that we need a novel approach to redefine optimal thyroid function ranges after considering disease risk in addition to population distribution and other variables, such as age and sex. Finally, even though this study provides significant data regarding variations within the thyroid function and effect on stroke, data in thyroid hormone users and whether similar associations occur are lacking.
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