Background: Elevated morning plasma cortisol is associated with multiple cardiovascular risk factors in metabolic syndrome. Epidemiological studies have also reported a positive association between plasma cortisol and coronary heart disease (CHD), although not all estimates are statistically significant (OR 1.10 (95% CI 0.97 to 1.25)) (Davey Smith et al. Circulation 2005). Importantly, observational studies are unable to infer causality and results may be confounded.
Methods: A two-sample Mendelian randomisation approach was used to estimate the causal effect of plasma cortisol on risk of CHD. A genetic instrument for plasma cortisol comprised three SNPs which were associated with plasma cortisol in the recent Cortisol Network (CORNET) genome wide association meta-analysis (n=12,597) (Bolton et al. PLoS Genetics 2014). We investigated the association between this genetic instrument for plasma cortisol and risk of CHD in up to 22,223 cases/64,762 controls from the publicly available CARDIOGRAM consortium.
Results: Each standard deviation rise in genetically predicted plasma cortisol was associated with an odds ratio of 1.27 (95% CI: 1.01 to 1.60) for CHD.
Conclusions: These results are compatible with a causal effect for the observational association between plasma cortisol and CHD. The inconsistent results from observational studies may be explained by: the inverse association between cortisol and obesity, which confounded the positive association of cortisol with other cardiovascular risk factors; and the use of single ‘snapshot’ plasma cortisol measurement rather than cumulative measure of cortisol exposure provided by genetic prediction. A bidirectional Mendelian randomisation analysis between plasma cortisol and BMI may yield greater clarity. Measurements of cortisol may add value to predictions of CHD risk.