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Genetic Thyrotropin Regulation of Atrial Fibrillation Risk Is Mediated Through an Effect on Height.

Authors
  • Shi, Mingjian1
  • Manouchehri, Ali M2
  • Shaffer, Christian M2
  • Vaitinadin, Nataraja Sarma2
  • Hellwege, Jacklyn N2
  • Salem, Joe-Elie3
  • Davis, Lea K2
  • Simmons, Jill H4
  • Roden, Dan M1, 2, 5
  • Shoemaker, M Benjamin2
  • Ferguson, Jane F2
  • Mosley, Jonathan D1, 2
  • 1 Department of Biomedical Informatics & Center for Precision Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
  • 2 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
  • 3 Département de Pharmacologie, APHP, Sorbonne Université, INSERM, UNICO-GRECO Cardio-oncology Program, F75013 Paris, France. , (France)
  • 4 Division of Pediatric Endocrinology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
  • 5 Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37212, USA.
Type
Published Article
Journal
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Publication Date
Jun 16, 2021
Volume
106
Issue
7
Pages
2124–2132
Identifiers
DOI: 10.1210/clinem/dgab272
PMID: 33895829
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

A genetic predisposition to lower thyrotropin (TSH) levels is associated with increased atrial fibrillation (AF) risk through undefined mechanisms. Defining the genetic mediating mechanisms could lead to improved targeted therapies to mitigate AF risk. 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. 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. 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. © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected]

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