Mendelian randomisation in cardiovascular research: an introduction for clinicians
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TLDR
A narrative review of the literature where Mendelian randomisation has provided pivotal information for drug discovery including predicting efficacy, informing on target-mediated adverse effects and providing potential new evidence for drug repurposing is conducted.Abstract:
Understanding the causal role of biomarkers in cardiovascular and other diseases is crucial in order to find effective approaches (including pharmacological therapies) for disease treatment and prevention. Classical observational studies provide naive estimates of the likely role of biomarkers in disease development; however, such studies are prone to bias. This has direct relevance for drug development as if drug targets track to non-causal biomarkers, this can lead to expensive failure of these drugs in phase III randomised controlled trials. In an effort to provide a more reliable indication of the likely causal role of a biomarker in the development of disease, Mendelian randomisation studies are increasingly used, and this is facilitated by the availability of large-scale genetic data. We conducted a narrative review in order to provide a description of the utility of Mendelian randomisation for clinicians engaged in cardiovascular research. We describe the rationale and provide a basic description of the methods and potential limitations of Mendelian randomisation. We give examples from the literature where Mendelian randomisation has provided pivotal information for drug discovery including predicting efficacy, informing on target-mediated adverse effects and providing potential new evidence for drug repurposing. The variety of the examples presented illustrates the importance of Mendelian randomisation in order to prioritise drug targets for cardiovascular research.read more
Citations
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Evaluating the potential role of pleiotropy in Mendelian randomization studies.
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Heard-Costa,Volker Hoesel,Jouke-Jan Hottenga,Åsa Johansson,Åsa Johansson,Toby Johnson,Shamika Ketkar,Claudia Lamina,Shengxu Li,Miriam F. Moffatt,Richard H. Myers,Narisu Narisu,John R. B. Perry,Marjolein Peters,Michael Preuss,Samuli Ripatti,Fernando Rivadeneira,Camilla H. Sandholt,Laura J. Scott,Nicholas J. Timpson,Jonathan Tyrer,Sophie van Wingerden,Richard M. Watanabe,Charles C. White,Fredrik Wiklund,Christina Barlassina,Daniel I. Chasman,Daniel I. Chasman,Mark E. Cooper,John-Olov Jansson,Robert Lawrence,Niina Pellikka,Inga Prokopenko,Jianxin Shi,Elisabeth Thiering,Helene Alavere,Maria Teresa Sciarrone Alibrandi,Peter Almgren,Alice M. Arnold,Thor Aspelund,Larry D. Atwood,Beverley Balkau,Anthony J. Balmforth,Amanda J. Bennett,Yoav Ben-Shlomo,Richard N. Bergman,Sven Bergmann,Heike Biebermann,Alexandra I. F. Blakemore,Tanja Boes,Lori L. Bonnycastle,Stefan R. Bornstein,Morris Brown,Thomas A. Buchanan,Fabio Busonero,Harry Campbell,Francesco P. 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References
More filters
Journal ArticleDOI
Bias in meta-analysis detected by a simple, graphical test
TL;DR: Funnel plots, plots of the trials' effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials.
Journal Article
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)
Anders G. Olsson,Jjv McMurray,Gudmundur Thorgeirsson,C Spaulding,J Slattery,Kalevi Pyörälä,Ole Faergeman,RA Wright,Kåre Berg,Lars Wilhelmsen,Terje R. Pedersen,Tatu A. Miettinen,Harvey D. White,John Kjekshus,Michael Gnant +14 more
Journal Article
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Commentary
TL;DR: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations.
Journal ArticleDOI
Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
Colin Baigent,Anthony C Keech,Patricia M. Kearney,L Blackwell,Georgina Buck,Christine Pollicino,Adrienne Kirby,T Sourjina,Richard Peto,Rory Collins,R. J. Simes +10 more
TL;DR: Statin therapy can safely reduce the 5-year incidence of major coronary events, coronary revascularisation, and stroke by about one fifth per mmol/L reduction in LDL cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics.
Journal ArticleDOI
UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age
Cathie Sudlow,John Gallacher,Naomi E. Allen,Valerie Beral,Paul Burton,John Danesh,Paul Downey,Paul Elliott,Jane Green,Martin J Landray,Bette Liu,Paul M. Matthews,Giok Ong,Jill P. Pell,Alan J. Silman,Alan Young,Tim Sprosen,Tim Peakman,Rory Collins +18 more
TL;DR: The UK Biobank is described, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.
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