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Separating the direct effects of risk factors for atherosclerotic cardiovascular disease from those mediated by type 2 diabetes

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

Posted 07 Aug 2021
medRxiv DOI: 10.1101/2021.08.05.21261658

Background: Type 2 diabetes and atherosclerotic cardiovascular disease share several risk factors. However, it is unclear whether the effect of these risk factors on liability to atherosclerotic cardiovascular disease is independent of their effect on liability to type 2 diabetes. Methods: We performed univariate Mendelian randomization to quantify the effects of continuous risk factors from the IEU OpenGWAS database on liability to three outcomes: type 2 diabetes, coronary artery disease, and peripheral artery disease, as well as the effects of liability to type 2 diabetes on the risk factors. We also performed two-step Mendelian randomization for mediation to estimate the mediating pathways between the risk factors, liability to type 2 diabetes, and liability to the atherosclerotic cardiovascular disease outcomes where possible. Results: We found evidence for 53 risk factors as causes of liability to coronary artery disease, including eight which were causes of liability to type 2 diabetes only and four which were consequences only. Except for fasting insulin and hip circumference, the direct and total effects from the two-step Mendelian randomization were similar. This suggests that the combination of these risk factors with liability to type 2 diabetes was unlikely to alter liability to coronary artery disease beyond their individual effects. We also found 13 risk factors that were causes of liability peripheral artery disease, including six which were causes of liability to type 2 diabetes only and four which were consequences only. Again, the direct and total effects were similar for these ten risk factors apart from fasting insulin. Conclusions: Most risk factors were likely to affect liability to atherosclerotic cardiovascular disease independently of their relationship with liability to type 2 diabetes. Control of modifiable risk factors therefore remains important for reducing atherosclerotic cardiovascular disease risk regardless of patient liability to type 2 diabetes.

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