Abstract

Aims

Observational evidence suggests associations between sex hormone levels and heart failure (HF). We used sex‐specific genetic variants associated with androgenic sex hormone profiles to investigate the causal relevance of androgenic sex hormone profiles on cardiac structure and function and HF using Mendelian randomization (MR).

Methods and results

Sex‐specific uncorrelated genome‐wide significant (P < 5 × 10−8) variants predicting sex hormone‐binding globulin (SHBG), total testosterone, and bioavailable testosterone were extracted from summary statistics of genome‐wide association study (GWAS) on 425 097 participants in the UK Biobank. Sex‐specific gene–outcome association estimates were computed for left ventricular ejection fraction (LVEF), left ventricular end‐diastolic and end‐systolic volumes (LVEDV and LVESV, respectively), left ventricular stroke volume (LVSV), cardiac index, and cardiac output in 11 528 female and 14 356 male UK Biobank Imaging Study participants and for incident or prevalent HF in an external cohort of 47 309 cases and 930 014 controls. Inverse‐variance weighted MR was the primary analysis method. In females, higher genetically predicted bioavailable testosterone was associated with lower LVEDV [β per nmol/L = −0.11 (−0.19 to −0.03), P = 0.006], lower LVESV [β = −0.09 (−0.17 to −0.01), P = 0.022], lower LVSV [β = −0.11 (−0.18 to −0.03), P = 0.005], lower cardiac output [β = −0.08 (−0.16 to 0.00), P = 0.046], and lower cardiac index [β = −0.08 (−0.16 to −0.01), P = 0.034] and a higher risk of HF [odds ratio 1.10 (1.01–1.19), P = 0.026] on external validation analysis in larger scale, sex‐adjusted GWAS data. Higher genetically predicted SHBG was associated with higher LVEDV [β per nmol/L = 0.17 (0.08–0.25), P = 2 × 10−4], higher LVESV [β = 0.13 (0.05–0.22), P = 0.003], and higher LVSV [β = 0.18 (0.08–0.28), P = 2 × 10−4]. In males, higher genetically predicted total and bioavailable testosterone was associated with lower LVESV [β = −0.07 (−0.12 to −0.02), P = 0.007] and LVEF [β = −0.11 (−0.18 to −0.04), P = 0.003], respectively.

Conclusions

This study supports a causal effect of pro‐androgenic sex hormone profiles in females on adverse markers of left ventricular structure and function typically associated with HF with preserved ejection fraction and with HF. There was weaker evidence of association in males.

Details

Title
Genetically predicted androgenic profiles and adverse cardiac markers: a sex‐specific Mendelian randomization study
Author
Chen, Jun Yu 1   VIAFID ORCID Logo  ; Ardissino, Maddalena 2 ; Reddy, Rohin K. 1 ; Mason, Amy Marie 3 ; Raisi‐Estabragh, Zahra 4 ; Di Angelantonio, Emanuele 5 ; Burgess, Stephen 6 ; Ng, Fu Siong 1 

1  National Heart and Lung Institute, Imperial College London, London, UK 
2  National Heart and Lung Institute, Imperial College London, London, UK, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK 
3  British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK, Heart and Lung Research Institute, University of Cambridge, Cambridge, UK 
4  William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UK, Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK 
5  British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK, Heart and Lung Research Institute, University of Cambridge, Cambridge, UK, National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK, British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK, Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK, Health Data Science Research Centre, Human Technopole, Milan, Italy 
6  British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK, Heart and Lung Research Institute, University of Cambridge, Cambridge, UK, Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK 
Pages
3525-3537
Section
Original Articles
Publication year
2023
Publication date
Dec 1, 2023
Publisher
Oxford University Press
e-ISSN
20555822
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1002/ehf2.14527
ProQuest document ID
2894294098
Copyright
© 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.