Genetically predicted plasma cortisol and common chronic diseases: A Mendelian randomization study

Area of Science:

• Endocrinology
• Genetics
• Epidemiology

Background:

• Cushing's syndrome involves high cortisol (hypercortisolaemia) and is linked to type 2 diabetes, hypertension, osteoporosis, depression, and schizophrenia.
• The causal link between moderate, lifelong hypercortisolaemia and these conditions in the general population remains unclear.

Purpose of the Study:

• To investigate the causal association between genetically predicted plasma cortisol and major comorbidities using Mendelian randomization.
• To explore potential mediating factors, such as obesity, in the cortisol-hypertension relationship.

Main Methods:

• Employed a two-sample, inverse-variance-weighted Mendelian randomization analysis.
• Utilized three cortisol-associated genetic variants in the SERPINA6/SERPINA1 region as instrumental variables.
• Conducted multivariable Mendelian randomization to assess mediation by waist circumference.

Main Results:

• A genetically predicted 1 SD increase in plasma cortisol was associated with higher odds of hypertension (OR: 1.12; 95% CI: 1.05-1.18).
• Elevated cortisol predicted increased systolic and diastolic blood pressure (MD: 0.03 SD change for both).
• No causal association was found with type 2 diabetes, osteoporosis, depression, or schizophrenia. The hypertension link was reduced when accounting for waist circumference.

Conclusions:

• Strong evidence supports a causal relationship between plasma cortisol levels and an increased risk of hypertension.
• Obesity may mediate the association between cortisol and hypertension.