Studies Support Causal Role for Thyroid Disease in AFib

Batya Swift Yasgur MA, LSW

February 12, 2019

Genetic approaches support a causal role for thyroid disease in atrial fibrillation (AF), two newly published studies suggest.

In one study, researchers conducted a phenome-wide study of more than 37,100 individuals using a genetic predictor of thyrotropin levels to identify genetically determined variation in thyroid-stimulating hormone (TSH) levels and AF risk.

The polygenic predictor showed that elevated thyrotropin, a hormone associated with hypothyroidism — even within the normal range — was associated with a decreased risk for AF, a finding that remained even after those with overt thyroid disease were excluded from the analysis.

"Genetically determined variations in thyroid function, even those which fall within a physiologically accepted 'normal' range, can still increase the risk for AF," lead author Joe-Elie Salem, MD, PhD, said in a statement.

Any decision to treat subclinical thyroid disease should account for this new evidence, as "antithyroid medications to treat hyperthyroidism may reduce AF risk [while] thyroid hormone replacement for hypothyroidism may increase AF risk," said Salem, who is associate professor, Sorbonne Université–INSERM, Clinical Pharmacology, Cardio-oncology, La Pitié-Salpêtrière, Paris, and adjust associate professor, Vanderbilt University Medical Center, Cardio-oncology, Clinical Pharmacology, Nashville, Tennessee.

A simultaneously published Mendelian randomization study of more than 55,100 individuals with AF and 482,296 referents showed that genetically increased FT3:FT4 ratio and hyperthyroidism were associated with an increased risk for AF, while thyrotropin within the reference range and hypothyroidism were inversely associated with a risk for AF.

"In contrast to the clinical belief, we did not find any association of genetically determined FT4 within the normal range with AF," lead author Christina Ellervik, MD, PhD, MSci, DMSci, assistant professor, Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Massachusetts, told | Medscape Cardiology.

"Rather, we found that the pituitary hormone TSH is a better marker for AF," said Ellervik, who is also associate professor, Division of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen.

Both studies were published online January 23 in JAMA Cardiology.

Phenome-Wide Study

"Thyroid hormone levels (free thyroxine [FT4] and free triiodothyronine [FT3]) are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland," Salem and colleagues write.

Thyrotropin is used to assess thyroid function because it can detect thyroid hormone abnormalities with higher sensitivity and specificity than FT4 or FT3, they explain.

Hyperthyroidism caused by thyroid gland disorders is characterized by low serum thyrotropin levels and, conversely, hypothyroidism is associated with high thyrotropin levels.

Thyroid hormone levels are "highly heritable," and multiple common single-nucleotide variants (SNVs) have been associated with thyrotropin levels, the authors note.

Longitudinal data from electronic health records (EHRs), used together with large-scale DNA collections, can define the disease spectrum associated with single or multiple genomic variants.

The researchers used a polygenic predictor of thyrotropin levels identified in a previously published genome-wide association study (GWAS) of North American and European participants to conduct their phenome-wide association study (PheWAS).

They conducted a phenome-wide scanning of 1318 phenotypes using EHR data from a cohort of 37,154 North American individuals of European ancestry.

This dataset "performs robustly for biomarkers discovery and validation," the authors note.

Included individuals were born prior to 1990 and all fell within 4 SDs for each of the two principle components, based on common SNVs for the subset that self-identified as white/non-Hispanic.

The researchers used two sets of SNVs associated with thyrotropin and derived from two independent previous datasets: the International SNVs set (n = 20) had been identified in 26,429 euthyroid patients of European ancestry in North America and Europe; and the Iceland thyrotropin SNVs set, previously identified in 27,758 Icelanders with an "insular genetic background."

However, for the discovery of PheWAS, the researchers used the first dataset because of its "extrinsic validity in a North American EHR cohort."

Summary statistics for AF were drawn from a meta-analysis performed by the Atrial Fibrillation Genetics (AFGen) Consortium.

The final sample consisted of a discovery population of 37,154 North Americans of European ancestry (52% male) that had been previously shown to be "effective for biomarkers discovery and characterization."

Based on these, the researchers generated a weighted polygenic risk score using SNVs weights from the GWAS data.

The expected thyrotropin level for each individual was computed using the polygenic risk score.

Risk Present Even in Normal Range

In a subset of 6797 individuals who had thyrotropin measurements and no thyroid disease, the estimated additive thyrotropin heritability was 0.31 ± 0.07.

The polygenic predictor was found to account for 5.8% of phenotypic variation and 18.6% of additive genetic heritability.

The researchers then used predicted thyrotropin values to conduct a PheWAS of 1318 clinical diagnoses (called phecodes).

They found that in the PheWAS, the thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR] 1.10; 95% CI, 1.07 1 14; P =  5 × 10−11), but inversely associated with diagnoses related to hyperthyroidism — specifically, toxic multimodal goiter and thyroid goiter (OR, 0.64; 95% CI, 0.54 - 0.74; P =  2 × 10−8) and nontoxic multimodal goiter (OR, 0.78; 95% CI, 0.73 - 0.83;  =  8 × 10−17).

AF/flutter was the top association from among nonthyroid associations (OR, 0.93; 95% CI, 0.9 - 0.95;   = 9 × 10−7).

The AF association persisted even when the researchers repeated the analyses after excluding 9801 individuals without any diagnoses of a thyroid-related disease.

A record review of a random sample of cases showed that the positive predictive values of the PheWAS case definitions for diagnoses of hypothyroidism, AF, and toxic multimodal goiter were 0.87, 0.97, and 0.73, respectively.

An inverse variance weighted average (IVWA meta-analysis using AF SNVs weights from a GWAS of 17,931 AF cases and 115,142 control subjects showed that each increase in predicted thyrotropin was associated with a decreased risk for AF (OR, 0.91; 95% CI, 0.84 - 0.99; P  =  .03).

A second SNV thyrotropin predictor derived from an independent Icelandic population yielded similar results, which did not change when two SNVs that did not reach genome-wide significance in the original Icelandic population were excluded.

Additional analysis shpwed that in individuals older than 55 years, there was an inverse association between thyrotropin and AF (OR, 0.91 per SD change in thyrotropin levels; 95% CI, 0.83 - 0.99; P  =  .04).

The findings "suggest a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for this increasingly common arrhythmia," the authors conclude.

Complex Process

Ellervik et al conducted their study because previous research had suggested that FT4, even within the reference range, subclinical hyperthyroidism, and overt primary hyperthyroidism are associated with an increased risk for AF, whereas overt and subclinical hypothyroidism are associated with a reduced risk for AF.

Although AF risk is highest at the time of diagnosis of hyperthyroidism, it persists despite antithyroid treatment, raising "the question of whether FT4 is on the causal pathway or instead a biomarker for the hyperthyroid-AF association," the authors write.

Regulation of thyroid function is "complex," involving the pituitary and hypothalamus, as well as feedback mechanisms that go beyond the thyroid itself, the authors note.

Thyrotropin, which is produced and released by the pituitary, induces the thyroid to release thyroxin, which then "circulates in equilibrium between a sequestered, protein-bound form and the bioavailable free form (FT4)."

FT4 is converted into the FT3 hormone in thyroidal and peripheral tissues, "a process than can be assessed by the circulating FT3:FT4 ratio," the authors continue.

FT3 binds to nuclear receptors with cardiac contractility and affects heart rate and rhythm.

"Thus, FT4 levels are only one measure of thyroid function, and its association with AF may not reflect a direct relationship, even if there is causality along the pituitary-thyroid-cardiac axis," the authors said.

"Biological evidence points toward FT3 being the biologically active hormone mediating the thyroid effects; however, the focus in epidemiological studies has been on FT4 and TSH," Ellervik said.

The genes implicated in FT4 levels are involved in thyroid development, thyroid hormone action and transport, intracellular mechanisms of hormone action, and metabolism of thyroid hormones.

Mendelian Analysis

In this study, the researchers sought to determine whether FT4 and thyrotropin levels within the reference range, FT3:FT4 ratio, hypothyroidism, thyroid peroxidase antibody levels, or hyperthyroidism are "on a direct pathway" for AF.

"Limitations of many nongenetic epidemiological studies include difficulties of establishing directionality of the factor investigated and the outcome [in other words, reverse causation]," Ellervik explained.

"It is something associated with both the factor investigated and the outcome which is causal (confounding), but not the factor itself, making the factor only a marker?" she queried.

To more carefully investigate the question, the researchers conducted a Mendelian randomization analysis "to overcome many of the problems in nongenetic studies," she said.

"We used common variation in known genes of thyroid function to examine the direct effect of thyroid hormones on AF."

Although Mendelian randomization "may not be definitely of causality like a clinical trial, but supportive," it may be "at least better than conventional nongenetic epidemiologic studies," she added.

Instrument-exposure associations (i.e., FT4, thyrotropin, FT3:FT4 ratio, hypothyroidism, TPOAb, and hyperthyroidism) were drawn from GWAS for thyroid traits among individuals of European ancestry.

The instrument–AF association focusing on common variants was drawn from the AFGen Consortium among individuals of European ancestry, consisting of 55,114 individuals with AF (7672 incident, 47,442 prevalent) and 482,295 referents.

No Direct Effect of Normal-Range FT4

In meta-analysis of multivariable-adjusted, observational study-level data, the pooled hazard ratio (HR) of FT4 for incident AF and for prevalent AF were 1.55 (95% CI, 1.09 - 2.20;  =  .02; I 2  =  76%) and 2.80 (95% CI, 1.42 - 5.54; P = .003; I 2  =  64%) respectively, although the latter showed evidence of bias.

In multivariable-adjusted random-effects meta-analyses, each increment in the GRSFT4 was associated with a 0.082 SD (standard error, 0.007) increase of standardized FT4 (P  <  .001).

In summary-level MR analysis, the IVW-RE OR for combined prevalent and incident AF per SD of FT4 within the reference range was 1.01 (95% CI, 0.89 - 1.14; P  =  .88).

Weighted median analysis was significant with OR for AF per SD of FTof 0.87 (95% CI, 0.79 - 0.95; P = .001).

Estimates for the individual FT4 instruments in summary-level analysis, however, "were not homogeneous," as reflected in the I 2 MR value of 81% (95% CI, 73% -86%; P  <  .001).

Not Rare

Unlike FT4, genetically predicted increased FT3:FT4 ratio by the C allele showed a significant increased risk for AF: every 1 SD increase was associated with an OR of 1.33 (95% CI, 1.08 - 1.63; P = .006).

The pooled HR of thyrotropin for incident AF was 1.00 (95% CI, 0.98 - 1.01; P  =  .87; I 2  =  23%), and the pooled OR for prevalent AF was 0.99 (95% CI, 0.97 - 1.02; P  =  .52; I 2 =  0%), although the association with incident AF showed some participation bias.

Those with genetically predicted high-normal thyrotropin had a lower risk for AF: a 1 SD increase in thyrotropin was inversely associated with AF with an IVW-RE OR of 0.88 (95% CI, 0.84 - 0.92; P  <  .001; I 2 MR =  27%).

Genetically predicted hypothyroidism was inversely associated with AF (IVW-RE OR, 0.94; 95% CI, 0.90 - 0.99;   = .009; I 2 MR  =  52%).

This association was significantly stronger among hypothyroid SNPs that were identified for association with thyrotropin than among those identified with autoimmune function.

A genetically predicted 1 SD increase in TPOAb was not shown to be associated with AF.

By contrast, genetically predicted hyperthyroidism was associated with AF (IVW-RE OR, 1.04; 95% CI, 0.99 - 1.10; P  =  .13; I 2 MR =  77%).

"It is difficult to generalize, but in general, genetic defects associated with thyroid disorders have mostly been thought of as rare," Ellervik commented.

"But in latest years, common variation in known genes regulating thyroid hormones have been discovered and we investigated those genes," she said.

Consider Potential AF in Treating Subclinical Hypothyroidism

Commenting for | Medscape Cardiology, Jason Roberts, MD, MAS, author of an accompanying editorial, said that the "findings from both studies suggest that thyroid function does causally affect the risk of developing AF and, hence, its modulation would be predicted to affect the risk of developing the arrhythmia."

Moreover, it was "particularly interesting that the altered risk of developing AF extended beyond overt hyper- and hypothyroidism to the full spectrum of thyroid activity within the normal range," said Roberts, who is assistant professor of medicine, Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada.

"At present, it seems unlikely that we would want to modulate thyroid function within the normal range to mitigate the risk of AF, due to the potential of multiple adverse events — it is far from a 'clean intervention,'" Roberts cautioned.

"However, there is currently much debate regarding the need to treat subclinical forms of hyper- and hypothyroidism," he noted.

"Findings from the current study serve to reinforce AF as being one of the factors that should be considered when evaluating the need to intervene on subclinical forms of thyroid disease," he added.

Ellervik noted that their study "adds is a deeper investigation and understanding of the molecular culprits of the relationship between thyroid hormones and AF."

The study by Salem et al was supported by FRM and the American Heart Association. Vanderbilt University Medical Center's BioVU projects are supported by numerous sources — institutional funding, private agencies, and federal grants — which are listed on the original paper. Salem reports receiving grants from Fondation Recherche Medicale during the conduct of the study. The other authors' disclosures are listed on the original paper. There was no direct funding for the study by Ellervik et al. Ellervik reports no conflicts of interest. The other authors' disclosures are listed on the original paper. Roberts reports being supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the Canadian Stroke Prevention Intervention Network, the Cardiac Arrhythmia Network of Canada, and the Marianne Barrie Philanthropic Fund.

JAMA Cardiology. Published online January 23, 2019. Salem abstract, Ellervik abstract, Editorial


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