Morning plasma cortisol as a cardiovascular risk factor: findings from prospective cohort and Mendelian randomization studies

Abstract

Objective: The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD).

Design and methods: Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses).

Results: In the two prospective nested case-control studies, logistic regression adjusting for sex, age, BMI, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR: 1.28 per 1 SD higher cortisol, 95% CI: 1.06-1.54). In the meta-analysis of prospective studies, the equivalent result was OR: 1.18, 95% CI: 1.06-1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR: 1.06, 95% CI: 0.98-1.15.

Conclusions: All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together, these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.

Figure 1

Meta-analysis of prospective multivariable regression association of morning plasma cortisol with cardiovascular disease. Meta-analysis provides evidence that a 1 s.d. increase of morning plasma cortisol is associated with 18% higher risk of later cardiovascular disease (odds ratio (OR) 1.18 95% CI 1.06–1.31, P = 0.002). The VIP, MONICA and MSP study consisted of 268 cases and 396 controls; the BWHHS consisted of 45 cases and 89 controls; the Caerphilly Study consisted of 320 cases and 2003 controls; the Vietnam study consisted of 63 cases and 4192 controls. The number of controls in the Caerphilly and Vietnam Experience studies was assumed to be all individuals who did not experience a CVD event or CVD death. An assumption was made that the standard deviation of cortisol in the Vietnam Experience Study was the same as the VIP, MONICA and MSP study; this allowed inclusion of the Vietnam Experience study. Bars represent individual study 95% confidence intervals, with a central block proportional to study size. The summary diamond represents the pooled effect size estimate and 95% CI. Weights are from random-effects analysis. ^aRegression model included age, survey date, cohort, smoking, BMI and sampling time. ^bRegression model included age, smoking, BMI and sampling time. ^cRegression model including age, smoking status, sampling time, adult social class, alcohol consumption, height, FEV1/height², fibrinogen (log transformed), white cell count (log transformed). ^dEstimate from unadjusted regression model.

Figure 2

Effect estimate of genetically elevated morning plasma cortisol on risk of CHD. The forest plot shows odds ratios and 95% confidence intervals for CHD per standard deviation increase in morning plasma cortisol. The overall genetic effect was estimated using random-effects meta-analysis of Wald ratio estimates. The genetic effect was estimated using data from the meta-analysis of 34,541 CHD cases and 261,984 controls from UK Biobank and 88,192 cases and 162,544 controls from CARDIoGRAMplusC4D (29).