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Differentiating Associations of Glycemic Traits with Atherosclerotic and Thrombotic Outcomes: Mendelian Randomization Investigation

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posted on 02.05.2022, 13:21 by Shuai Yuan, Amy M. Mason, Stephen Burgess, Susanna C. Larsson

 We conducted a Mendelian randomization analysis to differentiate associations of four glycemic indicators with a broad range of atherosclerotic and thrombotic diseases. Independent genetic variants associated with fasting glucose (FG), 2-h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) at the genome-wide significance threshold were used as instrumental variables. Summary-level data for 12 atherosclerotic and 4 thrombotic outcomes were obtained from large genetic consortia and the FinnGen and UK Biobank studies. Higher genetically-predicted glycemic traits were consistently associated with an increased risk of coronary atherosclerosis related diseases and symptoms. Genetically-predicted glycemic traits except HbA1c showed positive associations with peripheral artery disease risk. Genetically-predicted FI levels were positively associated with risk of ischemic stroke and chronic kidney disease. Genetically-predicted FG and 2hGlu were positively associated with the risk of large artery stroke. Genetically-predicted 2hGlu levels showed positive associations with the risk of small vessel stroke. Higher levels of genetically-predicted glycemic traits were not associated with increased risk of thrombotic outcomes. Most associations for genetically-predicted levels of 2hGlu and FI remained after adjusting for other glycemic traits. Increased glycemic status appears to increase risks of coronary and peripheral artery atherosclerosis, but not thrombosis.  


The study is funded by the Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), the Karolinska Institutet’s Research Foundation Grants (Grant number 2020-01842), the Swedish Research Council for Health, Working Life and Welfare (Forte; grant no. 2018‐00123), and the Swedish Research Council (Vetenskapsrådet; grant no. 2016-01042 and 2019-00977). SB is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). AMM is funded by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant 116074. This research was supported by core funding from the: United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7), British Heart Foundation (RG/13/13/30194; RG/18/13/33946) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) [*]. *The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Role of the Funder: Funders had no roles in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.