Abstract
BackgroundCortisol, 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.MethodsSingle nucleotide polymorphisms (SNPs) strongly (P < 5 × 10−6) and independently (r2 < 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.ResultsGenetically 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.ConclusionsContrary 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.
Highlights
Cortisol, a steroid hormone frequently used as a biomarker of stress, is associated with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM)
Association of genetically predicted cortisol with ischemic heart disease (IHD), ischemic stroke, T2DM, and other CVD risk factors Genetically predicted cortisol Single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10−6) and independently (r2 < 0.001) associated with morning fasting plasma/serum cortisol were used as genetic instrumental variables
Association of genetically predicted cortisol with IHD, ischemic stroke, T2DM, and other CVD risk factors A total of 547 single nucleotide polymorphism (SNP) for cortisol were reported by the CORtisol NETwork (CORNET), Shin genome-wide association studies (GWAS), and Long GWAS (Fig. 1)
Summary
A steroid hormone frequently used as a biomarker of stress, is associated with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Methods: Single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10−6) and independently (r2 < 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. Elevated cortisol elicits extensive physiological responses, including energy mobilization (via promoting blood glucose followed by breakdown of proteins and fat) and homeostasis maintenance (via inducing vasoconstriction and sodium retention) [6] It initially results in a loss of appetite and weight loss but, if prolonged, may promote over-eating and weight gain [7]. There are highly plausible biological pathways through which stress, through elevated cortisol, may impact CVD
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