Two genetic studies support causal relationship between thyroid function and AF
A mendelian randomization study and a phenome-wide association study suggest that genetically determined variation in thyroid function is a risk factor for AF, even within the physiological range.
Introduction and methodsLiterature - Salem et al, Ellervik et al. - JAMA Cardiol. 2018
Association of Thyroid Function Genetic Predictors With Atrial Fibrillation. A Phenome-Wide Association Study and Inverse-Variance Weighted Average Meta-analysis - Salem JE et al.
Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation. A Mendelian Randomization Study - Ellervik C et al.
Overt hyperthyroidism is known to contribute to a wide spectrum of morbidity including atrial fibrillation (AF), hypertension, heart failure, and cerebrovascular diseases [1]. Overt or subclinical hypothyroidism on the other hand, are associated with lower AF risk [2]. Thyroid function is clinically assessed by measuring thyrotropin, which regulates thyroid hormone levels (free thyroxine [FT4] and triodothyronine [FT3]), which are both produced by the pituitary gland. As a consequence of feedback inhibition, hyperthyroidism due to thyroid gland disorders is characterized by low serum thyrotropin (TSH) levels, and hypothyroidism by high thyrotropin levels [3].
Observational studies have previously identified associations between not only overt hypothyroidism and hyperthyroidism and AF, but also of subclinical forms of thyroid dysfunction and values within the normal reference range [2,4]. Thyroid hormone levels are highly heritable, and many single nucleotide polymorphisms (SNPs) have been identified that associate with thyrotropin levels.
Mendelian randomization analyses to evaluate the suitability of known clinical risk factors as potential targets for AF prevention, have revealed associations between genetic instruments for BMI and AF, suggesting that reducing the obesity epidemic may help for AF prevention [5].
One study by Salem et al. conducted a ‘phenome-wide’ association study to evaluate associations between a polygenic predictor of pituitary-secreted thyrotropin levels and 1318 clinical diagnoses. In phenome-wide association studies, a screen for associations is performed based on a single genotype, with a broad spectrum of clinical phenotypes, as opposed to a genome-wide association study in which associations are evaluated between a single clinical phenotype and a large number of genetic variants. For this analysis, the genotype for which associations with phenotypes were searched, was a polygenic predictor based on about 20 SNPs that have previously been shown to associate with thyrotropin levels. Data of 37.154 North-American individuals of European ancestry from 6 medical centers were used.
The other study by Ellervik et al. performed a mendelian randomization analysis focused on thyroid function and AF. They also developed additional genetic instruments of components of thyroid function other than thyrotropin, such FT4 (within the reference range), FT3:FT4 ratio, hypothyroidism, thyroid peroxidase antibody levels and hyperthyroidism. Study-level data of 7.679 AF cases and 49.233 controls and summary-level data for 55.114 AF cases and 482.295 controls were used. All cases and controls were of European ancestry.
Main results
Salem et al., identified AF/atrial flutter as the clinical phenotype that exhibited the strongest association with the polygenic predictor for thyrotropin (OR: 0.93, 95%CI: 0.90-0.95), after exclusion of thyroid conditions. This finding persisted when 9801 individuals with thyroid-related disease were excluded (OR: 0.91, 95%CI: 0.88-0.95).
The association between the polygenic predictor of thyrotropin levels and AF was corroborated in an inverse-variance weighted average meta-analysis using AF SNPs of summary-level data from a cohort of 17.931 AF cases and 115.142 controls from the AF genetics consortium. Each SD increase in predicted thyrotropin was associated with a lower AF risk (OR: 0.86, 95%CI: 0.79-0.93). Thyrotropin levels, directly measured in AF cases (n=745) and controls (n=1680) of >55 years old that fell within the normal range were inversely associated with AF risk (OR: 0.91, 95%CI: 0.83-0.99).
Ellervik et al. also found an inverse association between genetically determined thyrotropin and AF (OR: 0.88, 95%CI: 0.84-0.92). Moreover, they reported significant associations with AF between the genetic instruments for FT3:FT4 ratios (for each 1 SD predicted increase in ratio: OR: 1.33, 95%CI: 1.09-1.63) and genetically predicted hypothyroidism (OR: 0.94, 95%CI: 0.90-0.99). Results were similar for prevalent and incident AF.
The genetic instruments for FT4 and hyperthyroidism did not reveal a significant association with AF. While the genetic risk score for FT4 levels was positively associated with standardized FT4 levels, analysis of observational study-level data did reveal a significant HR of FT4 for incident AF of 1.55 (95%CI: 1.09-2.20) and for prevalent AF of 2.80 (95%CI: 1.42-5.54).
Conclusion
Thus, both studies suggest that the association between thyroid function and AF that had been found in observational studies, is causal. This implies that genetically determined variation in thyroid function is a risk factor for AF, even within a range considered physiologically normal, as the association was maintained when analyzed only in individuals not meeting clinical thresholds for diagnosis. Analysis of various thyroid-related factors suggested that FT4 levels in the reference range do not directly impact on the risk of AF. The pituitary-thyroid-cardiomyocyte axis does seem to be implicated though, considering the significant genetically determined effects of FT3-FT4 ratio, thyrotropin and hypothyroidism. The specific causal agent in the link between thyroid function and AF remains to be deciphered.
Editorial comment
In an editorial comment [6], Jason Roberts suggests that these findings raise the possibility that modification of the pituitary-thyroid axis may serve as a therapeutic tool for AF prevention and management. However, he also points out that given the ubiquitous dependence of organ systems on thyroid function, such modulation of thyroid activity requires nuanced decision making, which is in stark contrast with the uniformly beneficial effects that a weight loss strategy for AF prevention would infer.
He also comments on the efforts of Ellervik et al. to identify the specific molecular culprit(s) responsible for the relationship between thyroid function and AF. “Owing to the interdependence of the molecular constituents of the pituitary-thyroid axis, teasing out the specific culprit from within the presumed causal pathway may be challenging with mendelian randomization.” The authors found no evidence of horizontal pleiotrophy for the thyrotropin, FT4 and FT3:FT4 ratio genetic instruments, which refers to when the association of an instrumental genetic variable with the outcome is not exclusively mediated by the risk factor. Roberts notes that vertical pleiotropy may still be operative, given their serial presence in a functional pathway. This should be investigated with methods other than mendelian randomization.
He concludes by stating that both studies independently support that the observational association between thyroid function and AF may reflect a causal relationship. “The ubiquitous importance of thyroid function to physiological processes throughout the body complicates the potential to leverage modification of thyroid activity as an AF preventive strategy; however, the findings emphasize the relevance of considering AF when deciding to treat subclinical forms of thyroid disease.”
References
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6. Roberts JD. 2019. Thyroid Function and the Risk of Atrial Fibrillation. Exploring Potentially Causal Relationships Through Mendelian Randomization. JAMA Cardiol. Published online January 23, 2019. doi:10.1001/jamacardio.2018.4614