Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian Randomization

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Abstract

We examined whether specifically statins, of the major lipid modifiers (statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) have pleiotropic effects on ischemic heart disease (IHD) via testosterone in men or women. As a validation, we similarly assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone. Using previously published genetic instruments we conducted a sex-specific univariable and multivariable Mendelian randomization study in the UK Biobank, including 179918 men with 25410 IHD cases and 212080 women with 12511 IHD cases. Of these three lipid modifiers, only genetically mimicking the effects of statins in men affected testosterone, which partly mediated effects on IHD. Correspondingly, genetically mimicking effects of anakinra on testosterone and IHD presented a reverse pattern to that for statins. These insights may facilitate the development of new interventions for cardiovascular diseases as well as highlighting the importance of sex-specific explanations, investigations, prevention and treatment.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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C M Schooling

School of Public Health, The University of Hong Kong, Hong Kong, China

For correspondence
cms1@hku.hk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9933-5887
J V Zhao

School of Public Health, The University of Hong Kong, Hong Kong, China

Competing interests
The authors declare that no competing interests exist.
S L Au Yeung

School of Public Health, The University of Hong Kong, Hong Kong, China

Competing interests
The authors declare that no competing interests exist.
G M Leung

School of Public Health, The University of Hong Kong, Hong Kong, China

Competing interests
The authors declare that no competing interests exist.

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The authors declare that there was no funding for this work

Ethics

Human subjects: This study is analysis of summary data previously collected with full consent

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.