Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation A Mendelian Randomization Study
Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation A Mendelian Randomization Study
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DOI：
10.1001/jamacardio.2018.4635
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发表时间：
2019-02-01
期刊：
影响因子：
24
通讯作者：
Chasman, Daniel, I
中科院分区：
文献类型：
--
作者：
Ellervik, Christina;Roselli, Carolina;Chasman, Daniel, I
重要性增加游离甲状腺素（FT 4）和减少促甲状腺激素与房颤（AF）的风险增加在观察性研究，但直接参与是不明确的。目的评估潜在的直接参与甲状腺性状对AF。设计，设置。和参与者研究水平孟德尔随机化（MR）包括11项研究，和总结水平MR包括55 114 AF病例和482 295参考，所有的欧洲ancestry.EXPOSURES全基因组显着变异被用作标准化的FT 4和促甲状腺激素水平的参考范围内，标准化的三碘甲状腺原氨酸（FT 3）：FT 4比值，甲状腺功能减退症，标准化的甲状腺过氧化物酶抗体水平，和甲状腺功能亢进症的工具。孟德尔随机化在研究水平分析中使用遗传风险评分，或在2个样本MR中使用个体单核苷酸多态性作为汇总水平data.Main结局和指标流行和事件AF.RESULTS研究水平分析包括7679例AF患者和49233例参考（平均年龄[标准误]，62 [3]岁; 15859例男性[29.7%]）。在研究水平的随机效应荟萃分析中，FT 4水平的合并风险比（毫微克/分升）为1.55（95% CI，1.09-2.20; P = 0.02; I-2= 76%），在多变量校正分析中，普遍AF的合并比值比（OR）为2.80（95% CI，1.41-5.54; P = 0.003; I-2 = 64%）。FT 4遗传风险评分与FT（4）增加0.082 SD（标准误0.007; P <0.001）相关，但与偶发性AF（风险比0.84; 95%CI 0.62-1.14; P = 0.27）或普遍性AF（OR 132; 95%CI 0.64-2.73; P = 0.46）无关。同样，在总结水平的逆方差加权随机效应MR中，参考范围内的基于基因的FT 4与AF无关（OR，1.01; 95% CI，0.89-1.14; P = 0.88）。然而，基于基因的FT 3：FT（4）比值升高、促甲状腺激素在参考范围内升高和甲状腺功能减退与AF相关，其负方差加权随机效应OR分别为1.33（95%CI，1.08-1.63; P = .006）、0.88（95%CI，0.84-0.92; P < .001）和0.94（95%CI，0.90-0.99; P = .009），并且对水平多效性检验具有稳健性。然而，涉及自身免疫和甲状腺过氧化物酶抗体水平的甲减单核苷酸多态性亚组与AF无关。基于基因的甲亢与AF相关，MR-Egger OR为1.31（95% CI，1.05-1.63; P = .02），有水平多效性证据结论和相关性遗传性升高的FT 3：FT（4）比值和甲状腺功能亢进与AF增加相关，而参考范围内的FT 4与AF增加无关，参考范围内的促甲状腺激素升高和甲状腺功能减退与AF减少相关，支持涉及垂体-甲状腺-心脏轴的途径。
IMPORTANCE Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.OBJECTIVE To evaluate the potential direct involvement of thyroid traits on AF.DESIGN, SETTING. AND PARTICIPANTS Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.EXPOSURES Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.MAIN OUTCOMES AND MEASURES Prevalent and incident AF.RESULTS The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I-2= 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I-2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT(4 )by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 132; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT(4 )ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31(95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045).CONCLUSIONS AND RELEVANCE Genetically increased FT3:FT(4 )ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.