Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
Creators: name: Schmidt, Amand F.
name: Holmes, Michael V.
name: Preiss, David
name: Swerdlow, Daniel I.
name: Denaxas, Spiros
name: Fatemifar, Ghazaleh
name: Faraway, Rupert
name: Finan, Chris
name: Valentine, Dennis
name: Fairhurst-Hunter, Zammy
name: Hartwig, Fernando Pires
name: Horta, Bernardo Lessa
name: Hypponen, Elina
name: Power, Christine
name: Moldovan, Max
name: Van Iperen, Erik
name: Hovingh, Kees
name: Demuth, Ilja
name: Norman, Kristina
name: Steinhagen-Thiessen, Elisabeth
name: Demuth, Juri
name: Bertram, Lars
name: Lill, Christina M.
name: Coassin, Stefan
name: Willeit, Johann
name: Kiechl, Stefan
name: Willeit, Karin
name: Mason, Dan
name: Wright, John
name: Morris, Richard
name: Wanamethee, Goya
name: Whincup, Peter
name: Ben-Shlomo, Yoav
name: McLachlan, Stela
name: Price, Jackie F.
name: Kivimaki, Mika
name: Welch, Catherine
name: Sanchez-Galvez, Adelaida
name: Marques-Vidal, Pedro
name: Nicolaides, Andrew
name: Panayiotou, Andrie G.
name: Onland-Moret, N. Charlotte
name: Van Der Schouw, Yvonne T.
name: Matullo, Giuseppe
name: Fiorito, Giovanni
name: Guarrera, Simonetta
name: Sacerdote, Carlotta
name: Wareham, Nicholas J.
name: Langenberg, Claudia
name: Scott, Robert A.
name: Luan, Jian’an
name: Bobak, Martin
name: Malyutina, Sofia
name: Pająk, Andrzej
name: Kubinova, Ruzena
name: Tamosiunas, Abdonas
name: Pikhart, Hynek
name: Grarup, Niels
name: Pedersen, Oluf
name: Hansen, Torben
name: Linneberg, Allan
name: Jess, Tine
name: Cooper, Jackie
name: Humphries, Steve E.
name: Brilliant, Murray
name: Kitchner, Terrie
name: Hakonarson, Hakon
name: Carrell, David S.
name: McCarty, Catherine A.
name: Lester, Kirchner H.
name: Larson, Eric B.
name: Crosslin, David R.
name: De Andrade, Mariza
name: Roden, Dan M.
name: Denny, Joshua C.
name: Carty, Cara
name: Hancock, Stephen
name: Attia, John
name: Holliday, Elizabeth
name: Scott, Rodney
name: Schofield, Peter
name: O’Donnell, Martin
name: Yusuf, Salim
name: Chong, Michael
name: Pare, Guillaume
name: Van Der Harst, Pim
name: Said, M. Abdullah
name: Eppinga, Ruben N.
name: Verweij, Niek
name: Snieder, Harold
name: Christen, Tim
name: Mook-Kanamori, D. O.
name: Gustafsson, Stefan
name: Lind, Lars
name: Ingelsson, Erik
name: Pazoki, Raha
name: Franco, Oscar
name: Hofman, Albert
name: Uitterlinden, Andre
name: Dehghan, Abbas
name: Teumer, Alexander
name: Baumeister, Sebastian
name: Dörr, Marcus
name: Lerch, Markus M.
name: Völker, Uwe
name: Völzke, Henry
name: Ward, Joey
name: Pell, Jill P.
name: Meade, Tom
name: Christophersen, Ingrid E.
name: Maitland-Van Der Zee, Anke H.
name: Baranova, Ekaterina V.
name: Young, Robin
name: Ford, Ian
name: Campbell, Archie
name: Padmanabhan, Sandosh
name: Bots, Michiel L.
name: Grobbee, Diederick E.
name: Froguel, Philippe
name: Thuillier, Dorothée
name: Roussel, Ronan
name: Bonnefond, Amélie
name: Cariou, Bertrand
name: Smart, Melissa
name: Bao, Yanchun
name: Kumari, Meena
name: Mahajan, Anubha
name: Hopewell, Jemma C.
name: Seshadri, Sudha
name: Dale, Caroline
name: Costa, Rui Providencia E.
name: Ridker, Paul M.
name: Chasman, Daniel I.
name: Reiner, Alex P.
name: Ritchie, Marylyn D.
name: Lange, Leslie A.
name: Cornish, Alex J.
name: Dobbins, Sara E.
name: Hemminki, Kari
name: Kinnersley, Ben
name: Sanson, Marc
name: Labreche, Karim
name: Simon, Matthias
name: Bondy, Melissa
name: Law, Philip
name: Speedy, Helen
name: Allan, James
name: Li, Ni
name: Went, Molly
name: Weinhold, Niels
name: Morgan, Gareth
name: Sonneveld, Pieter
name: Nilsson, Björn
name: Goldschmidt, Hartmut
name: Sud, Amit
name: Engert, Andreas
name: Hansson, Markus
name: Hemingway, Harry
name: Asselbergs, Folkert W.
name: Patel, Riyaz S.
name: Keating, Brendan J.
name: Sattar, Naveed
name: Houlston, Richard
name: Casas, Juan P.
name: Hingorani, Aroon D.
Publisher: name: Apollo - University of Cambridge Repository
Year: 2019
Subjects: Research Article
Coronary artery disease
Genetic association studies
Mendelian randomisation
LDL-cholesterol
Phenome-wide association scan

description: Abstract: 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.