Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
J Clin Endocrinol Metab. 2021 Jun 16;106(7):e2521-e2526. doi: 10.1210/clinem/dgab219.
Atrial fibrillation (AF), cardiac arrhythmias, and related risk factors are common in patients with Cushing's syndrome, or clinical chronic hypercortisolism. While hypercortisolism may be associated with AF, this association has not yet been ascertained causally.
To determine whether plasma cortisol is causally associated with AF using a 2-sample Mendelian randomization (MR) design.
Three genetic variants in the SERPINA1/SERPINA6 locus and functionally associated with plasma cortisol were identified in the CORtisol NETwork consortium (12 597 participants). Summary-level genome-wide association study (GWAS) data for the associations between the cortisol-associated variants and AF were obtained from a GWAS meta-analysis of 6 studies (60 620 AF cases and 970 216 noncases) and the FinnGen consortium (17 325 AF cases and 97 214 noncases). The fixed-effects inverse-variance weighted approach accounting for genetic correlations between variants was used for analysis. Multivariable MR analyses were conducted to assess potential mediating effects of systolic blood pressure (SBP) and waist circumference (WC). Summary-level GWAS data for SBP and WC were obtained respectively from the International Consortium of Blood Pressure (757 601 participants) and the Genetic Investigation of ANthropometric Traits consortium (232 101 participants).
One standard deviation increase in genetically predicted plasma cortisol was associated with greater risk of AF (odds ratio [OR] 1.20, 95% CI 1.06-1.35). The association attenuated when adjusting for genetically predicted SBP and WC (OR 0.99, 95% CI 0.72-1.38).
Evidence derived from the MR study suggests a positive association between plasma cortisol and risk of AF, likely mediated through SBP and WC.
心房颤动（AF）、心律失常和相关危险因素在库欣综合征或临床慢性皮质醇增多症患者中很常见。虽然皮质醇增多症可能与 AF 有关，但这种关联尚未被确定为因果关系。
使用两样本孟德尔随机化（MR）设计来确定血浆皮质醇是否与 AF 存在因果关系。
在皮质醇网络联盟（12597 名参与者）中确定了 SERPINA1/SERPINA6 基因座中的三个与血浆皮质醇功能相关的遗传变异。从 6 项研究（60620 例 AF 病例和 970216 例非病例）和芬兰基因联盟（17325 例 AF 病例和 97214 例非病例）的 GWAS 荟萃分析中获得了与皮质醇相关变异体与 AF 之间关联的汇总水平全基因组关联研究（GWAS）数据。采用固定效应逆方差加权方法，同时考虑了变异体之间的遗传相关性。进行了多变量 MR 分析，以评估收缩压（SBP）和腰围（WC）的潜在中介作用。分别从国际血压遗传联盟（757601 名参与者）和人类体型特征遗传研究联盟（232101 名参与者）获得了 SBP 和 WC 的汇总水平 GWAS 数据。
与遗传预测的血浆皮质醇增加一个标准差相关，AF 风险增加（比值比[OR]1.20，95%置信区间[CI]1.06-1.35）。当调整遗传预测的 SBP 和 WC 时，该关联减弱（OR 0.99，95% CI 0.72-1.38）。
MR 研究的证据表明，血浆皮质醇与 AF 风险之间存在正相关关系，这种关系可能通过 SBP 和 WC 介导。
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