Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

Schmidt, Amand F; Holmes, Michael V; Preiss, David; Swerdlow, Daniel I; Denaxas, Spiros; Fatemifar, Ghazaleh; Faraway, Rupert; Finan, Chris; Valentine, Dennis; Fairhurst-Hunter, Zammy; Hartwig, Fernando Pires; Horta, Bernardo Lessa; Hypponen, Elina; Power, Christine; Moldovan, Max; van Iperen, Erik; Hovingh, Kees; Demuth, Ilja; Norman, Kristina; Steinhagen-Thiessen, Elisabeth; ... (2019). Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. BMC cardiovascular disorders, 19(1), p. 240. BioMed Central 10.1186/s12872-019-1187-z

Preview

Text Schmidt, 2019, Phenome_wide association analysis .pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (923kB) | Preview

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.

Interest & Impact

Downloads

114 since deposited on 08 Jan 2020
15 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item