Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM) CIC Paris-Est, AP-HP, Institute of Cardio metabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France.
JAMA Cardiol. 2019 Feb 1;4(2):136-143. doi: 10.1001/jamacardio.2018.4615.
Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF).
To determine the association between genetically determined thyrotropin levels and AF.
DESIGN, SETTING, AND PARTICIPANTS: This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry. North American individuals of European ancestry with longitudinal electronic health records were analyzed from May 2008 to November 2016. Analysis began March 2018.
Clinical diagnoses associated with a polygenic predictor of thyrotropin levels.
Genetically determined thyrotropin levels.
Of 37 154 individuals, 19 330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10-11) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10-8 for toxic multinodular goiter). Among nonthyroid associations, the top association was AF/flutter (OR, 0.93; 95% CI, 0.9-0.95; P = 9 × 10-7). When the analyses were repeated excluding 9801 individuals with any diagnoses of a thyroid-related disease, the AF association persisted (OR, 0.91; 95% CI, 0.88-0.95; P = 2.9 × 10-6). To replicate this association, we conducted an inverse-variance weighted average meta-analysis using AF single-nucleotide variant weights from a genome-wide association study of 17 931 AF cases and 115 142 controls. As in the discovery analyses, each SD increase in predicted thyrotropin was associated with a decreased risk of AF (OR, 0.86; 95% CI, 0.79-0.93; P = 4.7 × 10-4). In a set of AF cases (n = 745) and controls (n = 1680) older than 55 years, directly measured thyrotropin levels that fell within the normal range were inversely associated with AF risk (OR, 0.91; 95% CI, 0.83-0.99; P = .04).
This study suggests a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for AF. The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk.
甲状腺激素水平通过垂体产生的促甲状腺激素的反馈抑制来严格调节。甲状腺功能亢进症绝大多数是由于甲状腺疾病引起的，并且众所周知，它会导致广泛的心血管发病率，特别是越来越常见的心律失常心房颤动（AF）。
确定遗传决定的促甲状腺激素水平与 AF 之间的关联。
设计、地点和参与者：这项全表型关联研究扫描了 1318 个与先前发表的全基因组关联研究中确定的促甲状腺激素水平多基因预测因子相关的表型，该研究包括欧洲血统的参与者。从 2008 年 5 月到 2016 年 11 月，分析了具有纵向电子健康记录的北美欧洲血统个体。分析于 2018 年 3 月开始。
与促甲状腺激素水平多基因预测因子相关的临床诊断。
遗传决定的促甲状腺激素水平。
在 37154 名参与者中，有 19330 名（52%）为男性。促甲状腺激素多基因预测因子与甲状腺功能减退症呈正相关（优势比[OR]，1.10；95%CI，1.07-1.14；P = 5×10-11），与甲状腺功能亢进症相关的诊断呈负相关（OR，0.64；95%CI，0.54-0.74；P = 2×10-8，毒性多结节性甲状腺肿）。在非甲状腺相关疾病中，排名最高的是 AF/flutter（OR，0.93；95%CI，0.9-0.95；P = 9×10-7）。当排除了 9801 名有任何甲状腺相关疾病诊断的个体后，AF 关联仍然存在（OR，0.91；95%CI，0.88-0.95；P = 2.9×10-6）。为了复制这种关联，我们使用来自 17931 例 AF 病例和 115142 例对照的全基因组关联研究中 AF 单核苷酸变异权重进行了逆方差加权平均荟萃分析。与发现分析一样，预测促甲状腺激素每增加一个标准差，与 AF 风险降低相关（OR，0.86；95%CI，0.79-0.93；P = 4.7×10-4）。在一组年龄大于 55 岁的 AF 病例（n = 745）和对照（n = 1680）中，处于正常范围内的直接测量促甲状腺激素水平与 AF 风险呈负相关（OR，0.91；95%CI，0.83-0.99；P = .04）。
这项研究表明，在生理可接受的正常范围内，甲状腺功能的遗传决定变异是 AF 的一个风险因素。治疗亚临床甲状腺疾病的临床决策应将 AF 风险纳入其中，因为治疗甲状腺功能亢进的抗甲状腺药物可能会降低 AF 风险，而治疗甲状腺功能减退症的甲状腺激素替代可能会增加 AF 风险。
