Department of Biomedical Informatics & Center for Precision Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
J Clin Endocrinol Metab. 2021 Jun 16;106(7):2124-2132. doi: 10.1210/clinem/dgab272.
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.
促甲状腺激素（TSH）水平较低的遗传倾向与心房颤动（AF）风险增加有关，但具体机制尚不清楚。
明确遗传介导机制可导致改善靶向治疗以降低 AF 风险。
我们使用两样本 Mendelian 随机化（MR）检验 TSH 相关单核苷酸变异与 16 个候选介质之间的关联。然后，我们进行多变量 Mendelian 随机化（MVMR）分析，在调整与 TSH 显著相关的每个介质后，检验 TSH 与 AF 之间的遗传关联是否明显减弱。
在进行多次检验调整后，有四个候选介质（游离甲状腺素、收缩压、心率和身高）与遗传预测的 TSH 呈显著负相关。在 MVMR 分析中，身高调整显著降低了 TSH 与 AF 之间关联的幅度，从身高每标准差变化导致 AF 发生的频率从-0.12（标准误 0.02）降至-0.06（0.02）（P = 0.005）。调整其他候选介质并没有显著减弱这种关联。
TSH 与 AF 风险增加之间的遗传关联部分是由身高较高介导的。因此，TSH 变异的某些遗传机制可能通过影响生命早期身高的机制来导致 AF 风险增加，而这些机制与生命后期甲状腺激素水平升高所驱动的机制不同。
