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Plasma Cortisol and Risk of Atrial Fibrillation: A Mendelian Randomization Study.

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Lee, Wei-Hsuan 


CONTEXT: Atrial fibrillation (AF), cardiac arrhythmias, and related risk factors are common in patients with Cushing's syndrome, or clinical chronic hypercortisolism. While hypercortisolism may be associated with AF, this association has not yet been ascertained causally. OBJECTIVE: To determine whether plasma cortisol is causally associated with AF using a 2-sample Mendelian randomization (MR) design. METHODS: Three genetic variants in the SERPINA1/SERPINA6 locus and functionally associated with plasma cortisol were identified in the CORtisol NETwork consortium (12 597 participants). Summary-level genome-wide association study (GWAS) data for the associations between the cortisol-associated variants and AF were obtained from a GWAS meta-analysis of 6 studies (60 620 AF cases and 970 216 noncases) and the FinnGen consortium (17 325 AF cases and 97 214 noncases). The fixed-effects inverse-variance weighted approach accounting for genetic correlations between variants was used for analysis. Multivariable MR analyses were conducted to assess potential mediating effects of systolic blood pressure (SBP) and waist circumference (WC). Summary-level GWAS data for SBP and WC were obtained respectively from the International Consortium of Blood Pressure (757 601 participants) and the Genetic Investigation of ANthropometric Traits consortium (232 101 participants). RESULTS: One standard deviation increase in genetically predicted plasma cortisol was associated with greater risk of AF (odds ratio [OR] 1.20, 95% CI 1.06-1.35). The association attenuated when adjusting for genetically predicted SBP and WC (OR 0.99, 95% CI 0.72-1.38). CONCLUSION: Evidence derived from the MR study suggests a positive association between plasma cortisol and risk of AF, likely mediated through SBP and WC.



Atrial fibrillation, Cushing’s syndrome, Mendelian randomization, cortisol, Atrial Fibrillation, Blood Pressure, Cushing Syndrome, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Disease Risk Factors, Humans, Hydrocortisone, Mendelian Randomization Analysis, Odds Ratio, Polymorphism, Single Nucleotide, Transcortin, Waist Circumference, White People, alpha 1-Antitrypsin

Journal Title

J Clin Endocrinol Metab

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The Endocrine Society


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Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (RG/18/13/33946)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MC_UU_00002/7)
SCL acknowledges research support from the Swedish Research Council (Vetenskapsrådet, 2016-01042 and 2019-00977), the Swedish Research Council for Health, Working Life and Welfare (Forte, 2018-00123), and the Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20190247). SB is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). During the conduction of this study EA was supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant n° 116074 and is currently funded by the British Heart Foundation Programme Grant RG/18/13/33946. This work was supported by core funding from: the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)*. This work was also supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. *The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.