Mendelian randomization study suggests modest causal role for thyroid activity Thyroid problems may be causally linked to atrial fibrillation (Afib, AF), according to a Mendelian randomization study. Having genes for hyperthyroidism and elevated ratio of triiodothyronine to free thyroxine (FT3:FT4) was associated with increased AF, reported Christina Ellervik, MD, PhD, of Harvard Medical School in Boston, and colleagues in JAMA Cardiology. The inverse-variance weighted random-effects odds were a significant 33% increase for those with genetic variants for increased FT3:FT4 ratio, 12% lower with genes for high-normal thyrotropin, and 6% lower with variants for hypothyroidism. "Low thyrotropin, as an early sign of an overactive thyroid gland, with a concomitant increased FT3:FT4 ratio are genetically associated with AF," the researchers concluded. However, the findings did not support a direct effect of FT4 levels in the reference range on AF in the study population without evidence of thyroid disease. As expected, odds of prevalent and incident AF were significantly increased with higher measured levels of FT4 within the reference range, and the genetic risk score for FT4 was associated with circulating levels of it. But, FT4-related genetic risk was not significantly linked to AF. This finding may suggest "that the pituitary hormone TSH is a better marker for atrial fibrillation," Ellervik emphasized in an interview with MedPage Today. At the same time, "the current lack of additional genetic instruments, particularly for FT3, makes it difficult to infer a specific causal agent in the link between thyroid function and AF," her group wrote. Looking at the allelic randomization given at conception mimics a randomized clinical trial as the irreversible exposure to genotype "is typically less likely affected by confounding or reverse causation than conventional observational analyses," they noted. Prior epidemiologic research has shown observational relationships between AF and clinical conditions like obesity, thyroid dysfunction, and hypertension, but could not determine causal relationships, noted Jason Roberts, MD, MAS, of Western University in London, Ontario, in an accompanying editorial. Distinguishing causality from observational relationships "is critical given that interventions on factors external to a causal pathway are less likely to achieve the desired effect on the outcome," Roberts emphasized. "One possible outcome is personalized tailoring of thyroid function as an additional tool to modify AF risk," Roberts noted, adding: "Although not immediately clear how these findings could be leveraged for individuals with normal thyroid function, they may influence treatment strategies for subclinical forms of thyroid disease where there is discord regarding the merits of intervention." With the hypothesis that if circulating thyroid hormone levels are directly involved in the development of AF, then genetic variation influencing those levels should also be associated with AF risk, Ellervik's group did a summary-level analysis from 66 studies with 537,409 participants and with genetic risk scores in study-level analysis from 11 prospective cohort and cross-sectional studies with 56,912 participants. Data on the summary-level and study-level analyses were collected through the AF Genetics (AFGen) Consortium. Participants were of European ancestry. The researchers identified eight single nucleotide polymorphisms for hyperthyroidism, one for the FT3:FT4 ratio, 15 for hypothyroidism, 56 for thyrotropin within the reference range, 30 for FT4 within the reference range, and four for standardized thyroid peroxidase antibody levels (TPOAb) concentration. The researchers acknowledged the limitations of their work as unobserved pleiotropy was not addressed, findings were not generalizable beyond European ancestry, and there was overlap between the study-level samples and the larger AF genome-wide association studies sample for the summary-level and the study-level samples. "Given the divergence of the observational and MR [mendelian randomization] instrumental findings for FT4, there remains a need for more analysis, especially downstream of FT4 along the hypothalamic-pituitary-thyroid-cardiac axis. Our ability to draw mechanistic inferences downstream of FT4 was limited by the availability of only one instrument for the FT3:FT4 ratio and the lack of any instruments for FT3, although this hormone, as opposed to FT4, is transported into cardiomyocytes and thought to be more biologically relevant," the researchers wrote. "Despite the discovery of many genes for many thyroid hormones, their exact functions and role in AF are yet to be understood," said Ellervik. The study was funded by Roche Diagnostics. Roberts disclosed relationships with 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.