BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom.
PLoS One. 2022 Aug 19;17(8):e0272807. doi: 10.1371/journal.pone.0272807. eCollection 2022.
In observational studies, venous thromboembolism (VTE) has been associated with Cushing's syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization.
Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed.
Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62-0.87, p<0.001). The association was stronger for deep vein thrombosis (OR 0.69, 95% CI 0.55-0.88, p = 0.003) than for pulmonary embolism which did not achieve statistical significance (OR 0.83, 95% CI 0.63-1.09, p = 0.184). Adjusting for genetically predicted systolic blood pressure inverted the direction of the point estimate for VTE, although the resulting CI was wide (OR 1.06, 95% CI 0.70-1.61, p = 0.780).
This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for.
在观察性研究中，静脉血栓栓塞症（VTE）与库欣综合征和持续性精神压力有关，这两种情况都与更高的皮质醇水平有关。然而，目前尚不清楚在正常范围内的高皮质醇水平是否与 VTE 风险有因果关系。我们旨在使用孟德尔随机化评估血浆皮质醇水平与 VTE 风险之间的关联。
使用 SERPINA1/SERPINA6 基因座中的三个遗传变异（rs12589136、rs11621961 和 rs2749527）来代表血浆皮质醇。从 INVENT（28907 例病例和 157243 例非病例）和 FinnGen（6913 例病例和 169986 例非病例）联合体中获得与皮质醇相关的遗传变异与 VTE 的关联。FinnGen 联合体和英国生物银行提供了 VTE 亚型的相应数据。进行了两样本孟德尔随机化分析（逆方差加权法）。
遗传易感性导致更高的血浆皮质醇水平与 VTE 风险降低相关（每增加一个标准差的比值比 [OR] 为 0.73，95%置信区间 [CI] 为 0.62-0.87，p<0.001）。与深静脉血栓形成（OR 0.69，95%CI 0.55-0.88，p = 0.003）相比，这种关联在肺栓塞中更强，而肺栓塞未达到统计学意义（OR 0.83，95%CI 0.63-1.09，p = 0.184）。调整遗传预测的收缩压后，VTE 的点估计方向发生了反转，尽管所得 CI 较宽（OR 1.06，95%CI 0.70-1.61，p = 0.780）。
本研究提供了证据表明，正常范围内较高端的遗传预测血浆皮质醇水平与 VTE 风险降低相关，并且这种关联可能通过血压介导。本研究对皮质醇和 VTE 的观察性研究计划具有重要意义，表明应测量和考虑血压特征。
