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

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Lee, Wei-Hsuan 
Wood, Angela 
Di Angelantonio, Emanuele 
Butterworth, Adam S 

OBJECTIVE: Cushing's syndrome is characterized by hypercortisolaemia and is frequently accompanied by comorbidities such as type 2 diabetes, hypertension, osteoporosis, depression and schizophrenia. It is unclear whether moderate but lifelong hypercortisolaemia is causally associated with these diseases in the general population. We aimed to address this research gap using a Mendelian randomization approach. METHODS: We used three cortisol-associated genetic variants in the SERPINA6/SERPINA1 region as genetic instruments in a two-sample, inverse-variance-weighted Mendelian randomization analysis. We obtained summary-level statistics for cortisol and disease outcomes from publicly available genetic consortia, and meta-analysed them as appropriate. We conducted a multivariable Mendelian randomization analysis to assess potential mediating effects. RESULTS: A 1 standard deviation higher genetically predicted plasma cortisol was associated with greater odds of hypertension (odds ratio: 1.12; 95% confidence interval [CI]: 1.05-1.18) as well as higher systolic blood pressure (mean difference [MD]: 0.03 SD change; 95% CI: 0.01-0.05) and diastolic blood pressure (MD: 0.03 SD change; 95% CI: 0.01-0.04). There was no evidence of association with type 2 diabetes, osteoporosis, depression and schizophrenia. The association with hypertension was attenuated upon adjustment for waist circumference, suggesting potential mediation through central obesity. CONCLUSION: There is strong evidence for a causal association between plasma cortisol and greater risk for hypertension, potentially mediated by obesity.


Funder: Health Data Research UK

Funder: UK Medical Research Council

Funder: Economic and Social Research Council

Funder: Department of Health and Social Care (England)

Funder: Chief Scientist Office of the Scottish Government Health and Social Care Directorates

Funder: Health and Social Care Research and Development Division (Welsh Government)

Funder: Public Health Agency (Northern Ireland)

Funder: British Heart Foundation and Wellcome

Funder: Swedish Research Council for Health, Working Life and Welfare

Funder: Science and Technology Facilities Council

Funder: Sir Henry Dale Fellowship

Mendelian randomization, chronic diseases, cortisol, hypertension, major mental illness, osteoporosis, type 2 diabetes
Journal Title
Clin Endocrinol (Oxf)
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British Heart Foundation (None)
British Heart Foundation (None)
Engineering and Physical Sciences Research Council (EP/P020259/1)
Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (CH/12/2/29428)
British Heart Foundation (RG/18/13/33946)
National Institute for Health and Care Research (IS-BRC-1215-20014)