TY - JOUR
T1 - Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
AU - Schmidt, Amand F
AU - Holmes, Michael V
AU - Preiss, David
AU - Swerdlow, Daniel I
AU - Denaxas, Spiros
AU - Fatemifar, Ghazaleh
AU - Faraway, Rupert
AU - Finan, Chris
AU - Valentine, Dennis
AU - Fairhurst-Hunter, Zammy
AU - Hartwig, Fernando Pires
AU - Horta, Bernardo Lessa
AU - Hypponen, Elina
AU - Power, Christine
AU - Moldovan, Max
AU - van Iperen, Erik
AU - Hovingh, Kees
AU - Demuth, Ilja
AU - Norman, Kristina
AU - Steinhagen-Thiessen, Elisabeth
AU - Demuth, Juri
AU - Bertram, Lars
AU - Lill, Christina M
AU - Coassin, Stefan
AU - Willeit, Johann
AU - Kiechl, Stefan
AU - Willeit, Karin
AU - Mason, Dan
AU - Wright, John
AU - Morris, Richard
AU - Wanamethee, Goya
AU - Whincup, Peter
AU - Ben-Shlomo, Yoav
AU - McLachlan, Stela
AU - Price, Jackie F
AU - Kivimaki, Mika
AU - Welch, Catherine
AU - Sanchez-Galvez, Adelaida
AU - Marques-Vidal, Pedro
AU - Nicolaides, Andrew
AU - Panayiotou, Andrie G
AU - Onland-Moret, N Charlotte
AU - van der Schouw, Yvonne T
AU - Matullo, Giuseppe
AU - Fiorito, Giovanni
AU - Guarrera, Simonetta
AU - Hansen, Torben
AU - Linneberg, Allan
AU - Jess, Tine
AU - Christophersen, IE
AU - Lifelines Cohort authors
PY - 2019/10/29
Y1 - 2019/10/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074350493&partnerID=8YFLogxK
U2 - 10.1186/s12872-019-1187-z
DO - 10.1186/s12872-019-1187-z
M3 - Journal article
C2 - 31664920
SN - 1471-2261
VL - 19
SP - 240
JO - BMC Cardiovascular Disorders
JF - BMC Cardiovascular Disorders
IS - 1
M1 - 240
ER -