Clearer Genetic Link Between Thyroid Disorders and Atrial Fibrillation

Evidence tying an increased risk of cardiovascular events, particularly AF, in people with hypo- and hyperthyroidism, is gaining strength.

With Christina Ellervik, MD, PhD, and  Craig January, MD, PhD

Thyroid dysregulation has a near-ubiquitous effect throughout the body, including that of the heart. Previous studies introduced evidence of an association between thyroid disorders and atrial fibrillation (AF), with more recent data indicating that genetic markers play a stronger role in influencing cardiovascular health in patients with thyroid disease.1,2

As efforts to further individualize therapy and improve patient outcomes continue, more research has focused on the way thyroid disease might dictate the onset of AF and the potential benefit of genetic testing in assessing risk for AF in patients who have thyroid disease.

Growing genetic link ties thyroid disease to risk of AF.

Two separate studies,3,4 published in the Journal of the American Medical Association Cardiology, reported findings of an association between genetic determinants of AF in patients with thyroid disease.

Interrelationship between Thyroid Function and AF Gains Traction

“Thyroid disease (hyperthyroidism) and atrial fibrillation have a long history, and endocrinologists should be aware of this link,” said Craig January, MD, PhD, FACC, professor of cardiovascular medicine at the University of Wisconsin School of Medicine and Public Health in Madison, in reviewing the studies for EndocrineWeb. Dr. January chaired the writing group for the 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation.5

In fact, existing observational, longitudinal studies have established an association between an increased risk for AF and increased free thyroxine (fT4) within the standard reference range, subclinical hyperthyroidism, and overt primary hyperthyroidism.6

Dr. January cited genetic changes in ion channel mutations as a rare cause of AF. “The key is to recognize a familial pattern of atrial fibrillation, and if suspected, refer the patient to a cardiac inherited arrhythmias clinic or cardiac genetics team,” he told EndocrineWeb.

Historically, the predominating opinion in the medical community was that associated genetic defects [of hyperthyroidism and AF] were a rare occurrence, according to Christina Ellervik, MD, PhD, assistant professor of pathology at Boston Children's Hospital who was lead author of a study exploring the relationship between genetic determinants of AF and thyroid function; more recent findings suggest otherwise.4

Genetic Deep Dive into Link Between Thyroid Disease and AF

In the past few years, researchers have discovered a common variation in genes known to regulate thyroid hormones that may be responsible for an increased risk of cardiovascular disease in people who have been diagnosed with thyroid irregularities.

“We’ve investigated those genes and now, what this study adds is a deeper investigation into and a deeper understanding of the molecular culprits driving the relationship between thyroid hormones and AF,” Dr. Ellervik told EndocrineWeb.

Dr. Ellervik and her team employed the Mendelian ratio to assess whether certain known clinical risk factors might offer clues regarding the genetic correlation between thyroid pathogenesis and AF.4

The inclusion criteria for patients to be enrolled in the study were:

  • European ancestry contributing to the AGenn Consortium
  • Mean age of 53-76 years

Researchers pooled the genetic data from 56,912 study participants, 7,679 of whom had AF (2,093 cases with disease prevalence, and 5,586 individuals who were recently diagnosed/incidence) using data retrieved from 11 cross-sectional and prospective cohort studies contributing to the AGenn Consortium.4

Employing Mendelian randomization allowed investigators to evaluate whether certain known clinical risk factors might offer clues about the potential for thyroid pathogenesis of AF. Results revealed a pooled hazard ratio of free T4 (fT4) with an incident of 1.5 (95% CI, 1.09-2.20, P = 0.02).3

In a second study, investigators found no association of genetically determinant fT4 within the normal reference range, rather their results yielded data indicating that the pituitary production of TSH proven to be a better marker for AF.4

As Jason D. Roberts, MD, MAS, assistant professor of medicine at the University of Western Ontario, Canada, who authored an editorial on this topic in the same journal issue,7 pointed out, the results give rise to the “…possibility that modification of the pituitary-thyroid-cardiac axis may serve as a therapeutic tool for AF prevention and management.”

Historically, while aware of a possible genetic association with thyroid disorders, Dr. Ellervik said, the medical community has largely viewed genetics as rarely responsible for contributing to thyroid abnormalities. Yet, recent discoveries of genes that regulate thyroid function and these current findings suggest that the relationship is much stronger than previously acknowledged.

More significant, the understanding that thyroid disorder-induced AF was limited to hyperthyroidism has been challenged. In another recent study,5 which evaluated the genetic profiles of 37,154 individuals, the investigators found a positive correlation between thyrotropin polygenic predictor and hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10−11); however, investigators observed an inverse association between thyrotropin polygenic predictor and hyperthyroidism  (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10−8 for toxic multinodular goiter).4

The authors wrote that their findings signified a “role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for atrial fibrillation.”

Risk of AF Appears to Extend to Hypothyroidism Too

While some might find the genetic clues of thyroid disease as a possible marker for AF compelling, the data are limited to the study population.   

As such, said Dr. Ellervik, it should be noted that, while compelling, “these studies followed either exclusively or primarily European populations, so whether these findings might be extrapolated to people of color in the US warrants further investigation,” who added that another limitation of her study was that the function and effect of many newly identified thyroid hormones remained unclear.

These findings offer important insights regarding a connection between CVD risk and thyroid disease, but Dr. Ellervik conceded that despite an apparent genetic concordance between hyper- and hypothyroidism and AF, subjecting patients who have confirmed thyroid disease to genetic testing remains premature.

“Currently, we don’t yet know how appropriate it might be to evaluate the genetic profile of patients with confirmed thyroid disease to help assess their risk of AF,” she told EndocrineWeb. “We would need to study what a polygenic risk score [and add that] to the already known risk factors such as gender, age, alcohol use, body mass index [adiposity], hyperlipidemia, and circulating serum levels of thyroid hormones and thyrotropin.”

Furthermore, even with an evaluated risk score, before genetic testing were to be considered as a standard practice for appropriate patients, evaluation and due consideration would be warranted by key clinical endocrinology associations before clinicians might want to consider changing their current management practices in patients with thyroid disease—hypothyroidism or hyperthyroidism.

As is the norm, “the benefits of genetic testing should substantially outweigh the costs associated with testing before clinicians may entertain turning to this as a way of evaluating any clinical implications in their patients.”


close X