Physicians' Academy for Cardiovascular Education

PCSK9 variants have no effect on the risk of stroke

Differential effects of PCSK9 variants on risk of coronary disease and ischaemic stroke

Literature - Hopewell JC, et al. - Eur Heart J 2018;39:354–359

Main results


//PCSK9// genetic variants, that produce lower levels of LDL-c, are not associated with the risk of IS, in contrast to significant association with the risk of CHD.

Editorial comment

In his editorial article, Ference [6] focuses on the Mendelian randomization methodology, rather than the findings of the study published by Hopewell et al. He analyzes the limitations of the analogy of the so-called ‘nature’s randomized trials’ (Mendelian randomized study) and a randomized trial that include the translation of causal effect of lifelong changes in an exposure on an outcome to the expected effect in response to short-term therapeutically induced changes in that exposure on the outcome. He includes as well the danger of overestimating the expected effect size, when using Mendelian randomization outcomes to foresee the results of a randomized trial. The author concludes: ‘Mendelian randomization studies can be used to anticipate the results of randomized trials accurately. However, a common misconception is that a therapy directed against any causal exposure will probably improve the associated outcome. Unfortunately, finding that an exposure is causally associated with an outcome tells us almost nothing about whether a therapy directed against that exposure will improve the outcome in a randomized trial. To anticipate the results of a randomized trial, the critical question that must be answered is by how much the causal exposure must be changed to improve the associated outcome in a short-term randomized trial.’


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