Appraising the causal role of risk factors in coronary artery disease and stroke: A systematic review of Mendelian Randomization studies

Andrea Georgiou, Loukas Zagkos, Georgios Markozannes, Christos Chalitsios, Alexandros Asimakopoulos, Wei Xu, Lijuan Wang, Ines Mesa Eguiagaray, Xuan Zhou, Eleni Loizidou, Nikolaos Kretsavos, Evropi Theodoratou, Dipender Gill, Stephen Burgess, Evangelos Evangelou, Konstantinos K Tsilidis, Ioanna Tzoulaki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background: Mendelian randomization (MR) offers a powerful approach to study potential causal associations between exposures and health outcomes, by using genetic variants associated with an exposure as instrumental variables. In this systematic review, we aimed to summarize previous MR studies and to evaluate the evidence for causality for a broad range of exposures in relation to coronary artery disease (CAD) and stroke.

Methods and Results: MR studies investigating the association of any genetically predicted exposure with CAD or stroke were identified. Studies were classified into four categories, namely robust, probable, suggestive and insufficient, built on the significance of the main MR analysis results and its concordance with sensitivity analyses. Associations that did not perform any sensitivity analysis were classified as non-evaluable. We identified 2,725 associations eligible for evaluation, examining 535 distinct exposures. Of them, 141 were classified as robust, 353 as probable, 110 as suggestive and 926 had insufficient evidence. The most prominent robust associations were observed for anthropometric traits, lipids and lipoproteins and type 2 diabetes with CAD, clinical measurements with CAD and stroke, and thrombotic factors with stroke.

Conclusions: Despite the large number of studies that have been conducted, only a limited number of associations were supported by robust evidence. About half of the associations presented a MR sensitivity analysis along with the main analysis which further supported the causality of associations. Future research should focus on more thorough assessment of sensitivity MR analyses and further assessment of mediation effects or nonlinearity of associations.
Original languageEnglish
Number of pages14
JournalJournal of the American Heart Association
Early online date7 Oct 2023
Publication statusE-pub ahead of print - 7 Oct 2023

Keywords / Materials (for Non-textual outputs)

  • Mendelian randomization
  • systematic review
  • cardiovascular disease
  • evidence grading


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