Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation

Abstract

IMPORTANCE Increased free thyroxine (FT 4 ) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.OBJECTIVE To evaluate the potential direct involvement of thyroid traits on AF. DESIGN, SETTING, AND PARTICIPANTS Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.EXPOSURES Genomewide significant variants were used as instruments for standardized FT 4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT 3 ):FT 4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data. MAIN OUTCOMES AND MEASURES Prevalent and incident AF. RESULTSThe study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT 4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I 2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I 2 = 64%) in multivariable-adjusted analyses. The FT 4 genetic risk score was associated with an increase in FT 4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT 4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT 3 :FT 4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045). CONCLUSIONS AND RELEVANCEGenetically increased FT 3 :FT 4 ratio and hyperthyroidism, but not FT 4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

Mendelian Randomization analyses reveal a causal effect of thyroid function on stroke via atrial fibrillation

“…This is in line with the results of observational studies which have shown that AF is a major risk factor for stroke, increasing stroke risk up to five-fold (44). Our findings are also in line with recent studies showing that subjects with a genetically predicted higher TSH level have a lower risk of AF (40). While multiple pathophysiological pathways might be theoretically involved in the effect of thyroid function on stroke, we demonstrated that AF has a major role in mediating the effect of TSH within the reference range on the stroke risk.…”

“…The observed causal effect in the unadjusted analyses was independent of BMI, T2D, lipids, BP, HR and educational attainment which was used as a surrogate for socio-economic status (STable 10A, Fig 2). To further assess the effect of TSH on the risk of stroke via AF, we investigated whether the known effect of TSH on AF (40) is mediated by any risk factors. Multivariable MR analyses did not implicate BP, lipids, CAD, or T2D as possible mediators of the observed causal effect of TSH levels on AF risk (STable 11).…”

ALOX5,LPA,MMP9andTPOgene polymorphisms increase atherothrombosis susceptibility in middle-aged Mexicans

“…The remarkable HW departure found in TPO, along with the frequency differences between the groups, fortifies our results. Accordingly, other genetic determinants within the TPO, as in other genes involved in the thyroid function, have shown association with cardiovascular risk, suggesting a genetic influence through TH levels [74,75].…”

Free thyroxine within the normal reference range predicts risk of atrial fibrillation

“…The strongest association was found for AF/flutter. The study of Ellervik et al also included fT4 and fT3 in their analysis. In addition to confirming the findings of Salem et al, they reported a significant association between AF and fT3:fT4 ratio but not fT4 alone.…”