Comments on Mendelian randomization analysis
In a recent Mendelian randomization (MR) study, Xiao,et al 20 provided genetic and real-world
evidences about the protective role of PDE5 inhibition against ischemic
heart disease (IHD), and found the potential of these drugs to be
repurposed for IHD (CAD and AMI) prevention and treatment. Overall, this
study on MR analysis is indeed a good job. However, further
investigation, especially large-scale clinical trials are needed to
enhance its strength, since the dose-response effects of PDE5i from more
data on IHD prevention may provide additional information.
These excellent data in this study supported the protective role of
PDE5i on IHD and other cardiovascular outcomes by a MR analysis, which
offered the possibility of assessing causal relationships between
genetically predicted risk factors and acquired CVD. It is an optimal
study method to assess cardiovascular outcomes associated with risk
factors of interest. It’s believed that this study would be a new
example and an influential MR study, since it revealed the protective
role of PDE5 inhibition against IHD, and it is also pivotal for the
development of PDE5i due to lowering CVD risk in high-risk individuals.
In fact, there are indeed the opportunities and challenges of MR studies
for CAD, since MR analysis has tremendous potential for identifying
therapeutic targets that are likely to be causal for
CAD.21 And MR has been increasingly used not only to
predict the efficacy and safety of existing and novel drugs targeting
risk factors of CVD but also to develop the repurposing potential of
available PDE5i.22
As we know, there are the potential causal associations of lifestyle
factors with risk of CVD, particularly CAD and ischaemic stroke,
however, some MR studies indicated inconsistent results. On the one
hand, this phenomenon is probably a gap between single and comprehensive
risk factors; On the other hand, limitations of MR analysis are that
“genetic variants have life-long effects, whereas trials assess the
impact of short-term interventions”. Herein, “MR studies may not
reflect real-world practice, and trial endpoints often differ from
outcomes in MR analyses”.
However, in this study, Xiao, et al 20 added “a
real-world study”. Obviously, it enhanced the strengthen of this study.
At the same time, sensitivity analysis is one of the key steps for a
reliable and powerful MR study. Since MR analysis may help to evaluate
the repurposing potential of available PDE5i, no doubt, this study is an
excellent example. Of course, clinical trials are required to further
investigate the efficacy of PDE5i on preventing IHD at both the
population and the specific individual levels.