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

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


Low-density lipoprotein cholesterol (LDL-c) levels have been associated with coronary heart disease (CHD) and with ischemic stroke (IS), but the latter relationship is not well established [1]. PCSK9 variants are useful to study the strength of association between LDL-c and IS.I

n this study, the association of PCSK9 genetic variants with IS risk was evaluated, in more than 10,000 well-characterized IS cases, and the strength of association was compared with that of CHD risk. For this purpose, the following PCSK9 genetic variants were selected:

The effects of each variant on risk were examined separately and a weighted genetic risk score was constructed including only the two independent variants rs11591147 and rs505151.

Data from 3 genome-wide meta-analyses were used, which included 10,307 IS cases and 19,326 controls of European ancestry: the Global Lipids Genetics Consortium (GLGC) [10], the CARDIoGRAMPlusC4D Consortium [12], the METASTROKE Collaboration [13].

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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