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

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.

Keywords: cardiovascular; epidemiology; evolutionary biology; global health; none; pleiotropy; sex-specific; statin; testosterone.

Figure 1.. Directed acyclic graph showing the well-established protective effects of lipid modifiers and anti-inflammatories on IHD (solid lines) and possible additional pathways (dashed lines) investigated here.

Green indicates a lowering effect, red indicates an increasing effect.

Figure 2.. Schematic diagram showing the well-established protective effects of lipid modifiers on IHD (solid green lines) in the context of additional relevant pathways (green protective, red harmful) from an evolutionary biology perspective.

(Key: GnRH: gonadotropin releasing hormone, RBC: red blood cell, LDL: low density lipoprotein).