Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- Schmidt, A.F.
- Holmes, M.V.
- Preiss, D.
- Swerdlow, D.I.
- Denaxas, S.
- Fatemifar, G.
- Faraway, R.
- Finan, C.
- Valentine, D.
- Fairhurst-Hunter, Z.
- Hartwig, F.P.
- Horta, B.L.
- Hypponen, E.
- Power, C.
- Moldovan, M.
- Iperen, E. van
- Hovingh, K.
- Demuth, I.
- Norman, K.
- Steinhagen-Thiessen, E.
- Demuth, J.
- Bertram, L.
- Lill, C.M.
- Coassin, S.
- Willeit, J.
- Kiechl, S.
- Willeit, K.
- Mason, D.
- Wright, J.
- Morris, R.
- Wanamethee, G.
- Whincup, P.
- Ben-Shlomo, Y.
- McLachlan, S.
- Price, J.F.
- Kivimaki, M.
- Welch, C.
- Sanchez-Galvez, A.
- Marques-Vidal, P.
- Nicolaides, A.
- Panayiotou, A.G.
- Onland-Moret, N.C.
- Schouw, Y.T. van der
- Matullo, G.
- Fiorito, G.
- Guarrera, S.
- Sacerdote, C.
- Wareham, N.J.
- Langenberg, C.
- Scott, R.A.
- Luan, J.A.
- Bobak, M.
- Malyutina, S.
- Pajak, A.
- Kubinova, R.
- Tamosiunas, A.
- Pikhart, H.
- Grarup, N.
- Pedersen, O.
- Hansen, T.
- Linneberg, A.
- Jess, T.
- Cooper, J.
- Humphries, S.E.
- Brilliant, M.
- Kitchner, T.
- Hakonarson, H.
- Carrell, D.S.
- McCarty, C.A.
- Lester, K.H.
- Larson, E.B.
- Crosslin, D.R.
- Andrade, M. de
- Roden, D.M.
- Denny, J.C.
- Carty, C.
- Hancock, S.
- Attia, J.
- Holliday, E.
- Scott, R.
- Schofield, P.
- O'Donnell, M.
- Yusuf, S.
- Chong, M.
- Pare, G.
- Harst, P. van der
- Said, M.A.
- Eppinga, R.N.
- Verweij, N.
- Snieder, H.
- Christen, T.
- Mook-Kanamori, D.O.
- Gustafsson, S.
- Lind, L.
- Ingelsson, E.
- Pazoki, R.
- Franco, O.
- Hofman, A.
- Uitterlinden, A.
- Dehghan, A.
- Teumer, A.
- Baumeister, S.
- Dorr, M.
- Lerch, M.M.
- Volker, U.
- Volzke, H.
- Ward, J.
- Pell, J.P.
- Meade, T.
- Christophersen, I.E.
- Maitland-van der Zee, A.H.
- Baranova, E.V.
- Young, R.
- Ford, I.
- Campbell, A.
- Padmanabhan, S.
- Bots, M.L.
- Grobbee, D.E.
- Froguel, P.
- Thuillier, D.
- Roussel, R.
- Bonnefond, A.
- Cariou, B.
- Smart, M.
- Bao, Y.C.
- Kumari, M.
- Mahajan, A.
- Hopewell, J.C.
- Seshadri, S.
- Dale, C.
- Costa, R.P.E.
- Ridker, P.M.
- Chasman, D.I.
- Reiner, A.P.
- Ritchie, M.D.
- Lange, L.A.
- Cornish, A.J.
- Dobbins, S.E.
- Hemminki, K.
- Kinnersley, B.
- Sanson, M.
- Labreche, K.
- Simon, M.
- Bondy, M.
- Law, P.
- Speedy, H.
- Allan, J.
- Li, N.
- Went, M.
- Weinhold, N.
- Morgan, G.
- Sonneveld, P.
- Nilsson, B.
- Goldschmidt, H.
- Sud, A.
- Engert, A.
- Hansson, M.
- Hemingway, H.
- Asselbergs, F.W.
- Patel, R.S.
- Keating, B.J.
- Sattar, N.
- Houlston, R.
- Casas, J.P.
- Hingorani, A.D.
- Lifelines Cohort
- ICBP Consortium
- ISGC
DOIAbstract
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 ...
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