BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published 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. RESULTS: The 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. CONCLUSIONS: Genetic 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.

• Klíčová slova
• Genetic association studies, LDL-cholesterol, Mendelian randomisation, Phenome-wide association scan,
• MeSH
• anticholesteremika škodlivé účinky   terapeutické užití   MeSH
• biologické markery krev   MeSH
• celogenomová asociační studie MeSH
• cévní mozková příhoda epidemiologie   prevence a kontrola   MeSH
• down regulace MeSH
• dyslipidemie krev   farmakoterapie   epidemiologie   genetika   MeSH
• hodnocení rizik MeSH
• infarkt myokardu epidemiologie   prevence a kontrola   MeSH
• inhibitory serinových proteinas škodlivé účinky   terapeutické užití   MeSH
• ischemie mozku epidemiologie   prevence a kontrola   MeSH
• jednonukleotidový polymorfismus * MeSH
• LDL-cholesterol krev   MeSH
• lidé MeSH
• PCSK9 inhibitory * MeSH
• proproteinkonvertasa subtilisin/kexin typu 9 genetika   MeSH
• randomizované kontrolované studie jako téma MeSH
• rizikové faktory MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• anticholesteremika MeSH
• biologické markery MeSH
• inhibitory serinových proteinas MeSH
• LDL-cholesterol MeSH
• PCSK9 inhibitory * MeSH
• PCSK9 protein, human MeSH Prohlížeč
• proproteinkonvertasa subtilisin/kexin typu 9 MeSH