Abstract
BackgroundWe characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.MethodsPublished and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.ResultsThe PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable.ConclusionsGenetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
Highlights
We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9
The FOURIER and ODYSSEY OUTCOMES trials tested the efficacy of PCSK9-inhibition versus placebo on the background of statin treatment and both found that PCSK9 inhibition led to a 15% relative risk reduction of major vascular events in patients with established cardiovascular disease (CVD) and recent acute coronary syndrome over a median follow up of 2.2 to 2.8 years [6, 7]
Lipid and apolipoprotein associations As reported previously [14], the four PCSK9 SNPs were associated with lower low density lipoprotein-cholesterol (LDL-C) blood concentrations ranging from − 0.02 mmol/L per allele for rs11583680 to − 0.34 mmol/L for rs11591147 (See Additional file 2: Figure S1)
Summary
We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. The FOURIER and ODYSSEY OUTCOMES trials tested the efficacy of PCSK9-inhibition versus placebo on the background of statin treatment and both found that PCSK9 inhibition led to a 15% relative risk reduction of major vascular events in patients with established CVD and recent acute coronary syndrome over a median follow up of 2.2 to 2.8 years [6, 7]. Mendelian randomisation for target validation uses naturally-occurring variation in a gene encoding a drug target to identify mechanism-based consequences of pharmacological modification of the same target [8]. Such studies have previously proved useful in predicting success and failure in clinical trials and have assisted in delineating on-target from off-target actions of first-in-class drugs [9–
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