Association of Thyroid Function Genetic Predictors With Atrial Fibrillation A Phenome-Wide Association Study and Inverse-Variance Weighted Average Meta-analysis
Association of Thyroid Function Genetic Predictors With Atrial Fibrillation A Phenome-Wide Association Study and Inverse-Variance Weighted Average Meta-analysis
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DOI：
10.1001/jamacardio.2018.4615
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发表时间：
2019-02-01
期刊：
影响因子：
24
通讯作者：
Mosley, Jonathan D.
中科院分区：
文献类型：
--
作者：
Salem, Joe-Elie;Shoemaker, M. Benjamin;Mosley, Jonathan D.
重要提示甲状腺激素水平通过脑垂体产生的促甲状腺激素的反馈抑制而受到严格调节。甲状腺功能亢进症主要是由于甲状腺功能紊乱引起的，并且被公认为是导致广泛的心血管疾病发病率的原因，特别是日益常见的心律失常心房颤动（AF）。和参与者这一现象-一项广泛关联的研究扫描了1318种与促甲状腺激素水平的多基因预测因子相关的表型，广泛的关联研究，包括欧洲血统的参与者。从2008年5月至2016年11月，对具有纵向电子健康记录的欧洲血统的北美个体进行了分析。分析开始于2018年3月。主要结果和指标临床诊断与促甲状腺激素水平的多基因预测因子相关。暴露基因决定的促甲状腺激素水平。结果在37 154例个体中，19 330例（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呈正相关（比值比[OR] 1.10; 95%CI，1.07-114; P = 5 x 10（-11）），与甲状腺功能亢进相关诊断呈负相关（OR，0.64; 95%CI，0.54-0.74; P = 2 x 10（-8）毒性多结节性甲状腺肿）。在非甲状腺相关性中，最高相关性为AF/房扑（OR，0.93; 95%CI，0.9-0.95; P = 9 x 10 - 7）。当排除9801例诊断为甲状腺相关疾病的患者后，再次进行分析时，AF相关性持续存在（OR，0.91; 95%CI，0.88-0.95; P = 2.9 x 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的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，预测的促甲状腺激素每增加一个SD，房颤风险就降低（OR，0.86; 95%CI，0.79-0.93; P = 4.7 x 10 - 4）。在一组AF病例（n = 745）和对照组中（n = 1680）年龄大于55岁，直接测量的促甲状腺激素水平在正常范围内与AF风险呈负相关（OR，0.91; 95% CI，0.83-0.99; P = 0.04）结论和相关性这项研究表明，在生理上可接受的正常范围内，遗传决定的甲状腺功能变异是一个危险因素治疗亚临床甲状腺疾病的临床决策应包括AF的风险，因为治疗甲状腺功能亢进症的抗甲状腺药物可能会降低AF风险，而甲状腺功能减退症的甲状腺激素替代治疗可能会增加AF风险。
IMPORTANCE 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).OBJECTIVE 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.MAIN OUTCOMES AND MEASURES Clinical diagnoses associated with a polygenic predictor of thyrotropin levels.EXPOSURES Genetically determined thyrotropin levels.RESULTS 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, 1.07-114; P = 5 x 10(-11)) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 x 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 x 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 x 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 931AF cases and 115142 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 x 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).CONCLUSIONS AND RELEVANCE 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.