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

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology

UniBE Contributor:

Willeit, Karin Christine

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1471-2261

Publisher:

BioMed Central

Language:

English

Submitter:

Chantal Kottler

Date Deposited:

08 Jan 2020 09:27

Last Modified:

12 Jan 2020 02:43

Publisher DOI:

10.1186/s12872-019-1187-z

PubMed ID:

31664920

Uncontrolled Keywords:

Genetic association studies LDL-cholesterol Mendelian randomisation Phenome-wide association scan

BORIS DOI:

10.7892/boris.137329

URI:

https://boris.unibe.ch/id/eprint/137329

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