The role of cortisol in ischemic heart disease, ischemic stroke, type 2 diabetes, and cardiovascular disease risk factors: a bi-directional Mendelian randomization study

• Published in: BMC medicine Vol. 18; no. 1; p. 363
• Main Authors: Kwok, Man Ki, Kawachi, Ichiro, Rehkopf, David, Schooling, Catherine Mary
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.11.2020; BioMed Central; BMC
• Subjects: Adipose tissue; Age; Biobanks; Biomarkers; Biomarkers - blood; Blood pressure; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - etiology; Confidence intervals; Consortia; Coronary artery disease; Corticosteroids; Cortisol; Development and progression; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - etiology; Fasting; Female; Genomes; Glucose; Health aspects; Health risks; Heart diseases; Hormones; Humans; Hydrocortisone - pharmacology; Hydrocortisone - therapeutic use; Insulin; Ischemia; Ischemic Stroke - etiology; Lipids; Male; Mendelian randomization; Mendelian Randomization Analysis - methods; Meta-analysis; Metabolomics; Middle Aged; Myocardial ischemia; Myocardial Ischemia - etiology; Nucleotides; Physiological aspects; Plasma; Polymorphism, Single Nucleotide - genetics; Product development; Randomization; Risk analysis; Risk Factors; Sensitivity analysis; Single-nucleotide polymorphism; Statistical analysis; Steroids; Stress (Psychology); Stroke; Stroke (Disease); Type 2 diabetes; China; United Kingdom > UK; Cardiovascular disease; Cortisol; Diabetes; Mendelian randomization; Risk factors
• ISSN: 1741-7015; 1741-7015
• 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.