Separating the direct effects of traits on atherosclerotic cardiovascular disease from those mediated by type 2 diabetes

Venexia M Walker,Benjamin F Voight,Neil M Davies,Tom R Gaunt,Miriam S Udler,Michael G Levin,Marijana Vujkovic,Scott M Damrauer,Alice R Carter,George Davey Smith

doi:10.1007/s00125-022-05653-1

Abstract

Aims/hypothesisType 2 diabetes and atherosclerotic CVD share many risk factors. This study aimed to systematically assess a broad range of continuous traits to separate their direct effects on coronary and peripheral artery disease from those mediated by type 2 diabetes.MethodsOur main analysis was a two-step Mendelian randomisation for mediation to quantify the extent to which the associations observed between continuous traits and liability to atherosclerotic CVD were mediated by liability to type 2 diabetes. To support this analysis, we performed several univariate Mendelian randomisation analyses to examine the associations between our continuous traits, liability to type 2 diabetes and liability to atherosclerotic CVD.ResultsEight traits were eligible for the two-step Mendelian randomisation with liability to coronary artery disease as the outcome and we found similar direct and total effects in most cases. Exceptions included fasting insulin and hip circumference where the proportion mediated by liability to type 2 diabetes was estimated as 56% and 52%, respectively. Six traits were eligible for the analysis with liability to peripheral artery disease as the outcome. Again, we found limited evidence to support mediation by liability to type 2 diabetes for all traits apart from fasting insulin (proportion mediated: 70%).Conclusions/interpretationMost traits were found to affect liability to atherosclerotic CVD independently of their relationship with liability to type 2 diabetes. These traits are therefore important for understanding atherosclerotic CVD risk regardless of an individual’s liability to type 2 diabetes.Graphical abstract

Highlights

Type 2 diabetes shares several risk factors with the atherosclerotic CVDs coronary artery disease and peripheral artery disease
Ethics approval This research using UK Biobank data was completed under Application Number 15825, which has been subject to ethics approval. The results of this analysis are presented in four parts: (1) the selection of traits from the IEU OpenGWAS database [17]; (2) the results of the univariate Mendelian randomisation analyses to interrogate the effect of each trait on liability to type 2 diabetes and the effect of liability to type 2 diabetes on each trait; (3) the results related to liability to coronary artery disease from both the univariate Mendelian randomisation and two-step Mendelian randomisation for mediation; and (4) results related to liability to peripheral artery disease from the univariate Mendelian randomisation and two-step Mendelian randomisation for mediation
Using univariate Mendelian randomisation, we provide evidence for the causal effects of multiple traits on liability to our three outcomes of interest: type 2 diabetes; coronary artery disease; and peripheral artery disease, (Fig. 4)

Summary

Introduction

Type 2 diabetes shares several risk factors with the atherosclerotic CVDs coronary artery disease and peripheral artery disease. Two-step Mendelian randomisation for mediation analysis is an extension to this method and incorporates the causal effect of a mediator, to estimate the direct (independent of the mediator) and indirect (via the mediator) effects of an exposure on an outcome [8, 9]. This approach can be applied using summary statistics from multiple genome-wide association studies (GWASs) with non-overlapping samples [10]. This removes the need for individual-level data from a single study containing information on all the risk factors, allowing broad systematic assessment of a wide range of risk factors unlikely to be captured in one place

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