Abstract
Aims PCSK9 genetic variants that have large effects on low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD) have prompted the development of therapeutic PCSK9-inhibition. However, there is limited evidence that PCSK9 variants are associated with ischaemic stroke (IS).Methods and resultsAssociations of the loss-of-function PCSK9 genetic variant (rs11591147; R46L), and five additional PCSK9 variants, with IS and IS subtypes (cardioembolic, large vessel, and small vessel) were estimated in a meta-analysis involving 10 307 IS cases and 19 326 controls of European ancestry. They were then compared with the associations of these variants with LDL-C levels (in up to 172 970 individuals) and CHD (in up to 60 801 CHD cases and 123 504 controls). The rs11591147 T allele was associated with 0.5 mmol/L lower LDL-C level (P = 9 × 10−143) and 23% lower CHD risk [odds ratio (OR): 0.77, 95% confidence interval (CI): 0.69–0.87, P = 7 × 10−6]. However, it was not associated with risk of IS (OR: 1.04, 95% CI: 0.84–1.28, P = 0.74) or IS subtypes. Information from additional PCSK9 variants also indicated consistently weaker effects on IS than on CHD.Conclusion PCSK9 genetic variants that confer life-long lower PCSK9 and LDL-C levels appear to have significantly weaker, if any, associations with risk of IS than with risk of CHD. By contrast, similar proportional reductions in risks of IS and CHD have been observed in randomized trials of therapeutic PCSK9-inhibition. These findings have implications for our understanding of when Mendelian randomization can be relied upon to predict the effects of therapeutic interventions.
Highlights
The causal association between low-density lipoprotein cholesterol (LDL-C) level and coronary heart disease (CHD) risk is well established
Summary results for LDL-C have been contributed by the Global Lipids Genetics Consortium, downloaded at http://csg.sph.umich.edu// abecasis/public/lipids2013/
Results for ischaemic stroke have been contributed by the International Stroke Genetics Consortium METASTROKE collaboration, with acknowledgements to each of the contributing studies provided in the Supplementary material
Summary
The causal association between low-density lipoprotein cholesterol (LDL-C) level and coronary heart disease (CHD) risk is well established. The observational and randomized evidence for the associations of LDL-C with ischaemic stroke (IS) risk is contrasting. LDL-C is much more weakly associated with IS than with CHD (about 10% vs 30% lower relative risk per 1 mmol/L lower LDL-C).[1] By contrast, in randomized controlled trials, statin therapy that lowered LDL-C levels for about 5 years has been found to produce similar proportional reductions in the risks of IS and CHD (20–25% per 1 mmol/L LDL-C reduction).[2] Ezetimibe, which lowers LDL-C by a different mechanism to statins, reduces risk of IS.[3] Whereas observational studies of a risk factor may be prone to confounding and other biases, the specific treatment assessed in a randomized trial may have effects beyond those produced by modifying the particular risk factor
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