School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1/F, Patrick Manson Building (North Wing), 7 Sassoon Road, Hong Kong Special Administrative Region, China.
Department of Social and Behavioral Sciences, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
BMC Med. 2020 Nov 27;18(1):363. doi: 10.1186/s12916-020-01831-3.
Cortisol, a steroid hormone frequently used as a biomarker of stress, is associated with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). To clarify whether cortisol causes these outcomes, we assessed the role of cortisol in ischemic heart disease (IHD), ischemic stroke, T2DM, and CVD risk factors using a bi-directional Mendelian randomization (MR) study.
Single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10) and independently (r < 0.001) predicting cortisol were obtained from the CORtisol NETwork (CORNET) consortium (n = 12,597) and two metabolomics genome-wide association studies (GWAS) (n = 7824 and n = 2049). They were applied to GWAS of the primary outcomes (IHD, ischemic stroke and T2DM) and secondary outcomes (adiposity, glycemic traits, blood pressure and lipids) to obtain estimates using inverse variance weighting, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. Conversely, SNPs predicting IHD, ischemic stroke, and T2DM were applied to the cortisol GWAS.
Genetically predicted cortisol (based on 6 SNPs from CORNET; F-statistic = 28.3) was not associated with IHD (odds ratio (OR) 0.98 per 1 unit increase in log-transformed cortisol, 95% confidence interval (CI) 0.93-1.03), ischemic stroke (0.99, 95% CI 0.91-1.08), T2DM (1.00, 95% CI 0.96-1.04), or CVD risk factors. Genetically predicted IHD, ischemic stroke, and T2DM were not associated with cortisol.
Contrary to observational studies, genetically predicted cortisol was unrelated to IHD, ischemic stroke, T2DM, or CVD risk factors, or vice versa. Our MR results find no evidence that cortisol plays a role in cardiovascular risk, casting doubts on the cortisol-related pathway, although replication is warranted.
皮质醇作为一种常用于评估压力的类固醇激素，与心血管疾病（CVD）和 2 型糖尿病（T2DM）有关。为了明确皮质醇是否会导致这些结果，我们采用双向孟德尔随机化（MR）研究，评估皮质醇在缺血性心脏病（IHD）、缺血性卒中、T2DM 及 CVD 危险因素中的作用。
从 CORtisol NETwork（CORNET）联盟（n=12597）和两项代谢组学全基因组关联研究（GWAS）（n=7824 和 n=2049）中获得了强关联（P<5×10）和独立（r<0.001）预测皮质醇的单核苷酸多态性（SNP）。将这些 SNP 应用于主要结局（IHD、缺血性卒中和 T2DM）和次要结局（肥胖、血糖特征、血压和血脂）的 GWAS，采用逆方差加权法、加权中位数法、MR-Egger 法和 MR-PRESSO 法进行估计，并作为敏感性分析。相反，我们将预测 IHD、缺血性卒中和 T2DM 的 SNP 应用于皮质醇 GWAS。
基于 CORNET 中的 6 个 SNP（F 统计量=28.3）预测的皮质醇与 IHD（每增加一个单位 log 转化皮质醇的比值比（OR）0.98，95%置信区间（CI）0.93-1.03）、缺血性卒中（OR 0.99，95%CI 0.91-1.08）、T2DM（OR 1.00，95%CI 0.96-1.04）或 CVD 危险因素均无相关性。预测的 IHD、缺血性卒中和 T2DM 与皮质醇也无相关性。
与观察性研究相反，基于遗传预测的皮质醇与 IHD、缺血性卒中、T2DM 或 CVD 危险因素之间无关联，反之亦然。我们的 MR 结果没有发现皮质醇在心血管风险中起作用的证据，这对皮质醇相关途径提出了质疑，尽管需要进一步的复制研究。
