Genetic Thyrotropin Regulation of Atrial Fibrillation Risk Is Mediated Through an Effect on Height
Year: 2021
Type: article
Study design: Observational Study
Abstract: CONTEXT: A genetic predisposition to lower thyrotropin (TSH) levels is associated with increased atrial fibrillation (AF) risk through undefined mechanisms. OBJECTIVE: Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk. METHODS: We used 2-sample mendelian randomization (MR) to test associations between TSH-associated single-nucleotide variations and 16 candidate mediators. We then performed multivariable mendelian randomization (MVMR) to test for a significant attenuation of the genetic association between TSH and AF, after adjusting for each mediator significantly associated with TSH. RESULTS: Four candidate mediators (free thyroxine, systolic blood pressure, heart rate, and height) were significantly inversely associated with genetically predicted TSH after adjusting for multiple testing. In MVMR analyses, adjusting for height significantly decreased the magnitude of the association between TSH and AF from -0.12 (SE 0.02) occurrences of AF per SD change in height to -0.06 (0.02) (P = .005). Adjusting for the other candidate mediators did not significantly attenuate the association. CONCLUSION: The genetic association between TSH and increased AF risk is mediated, in part, by taller stature. Thus, some genetic mechanisms underlying TSH variability may contribute to AF risk through mechanisms determining height occurring early in life that differ from those driven by thyroid hormone-level elevations in later life.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: American Heart Association, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G136028025, G1616567724, G1967470738, Understanding the genetic risk underlying racial disparities in uterine fibroids, G2247587933, G2310098089, G2328519459, G25420283, G3420921512, BioVU Plasma Storage Equipment, Genetic Epidemiology of Multiple Sclerosis, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, Delineating epidemiological and genetic factors associated with cardiac diastolic dysfunction, Building Interdisciplinary Research Careers in Women's Health, G7464576769, The Vanderbilt Institute for Clinical and Translational Research (VICTR), Roden Population Project: Identifying AF subtypes driven by inflammation, Vanderbilt Genome Electronic Records Project, Epidemiologic Architecture for Genes Linked to Environment (EAGLE), G9000119601, Vanderbilt Institute for Clinical and Translational Research (VICTR), Clinical Pharmacology Training Program, G949362299, G95160140
OpenAlex ID: W3157755628