Journal Article

DKFZ-2019-02517

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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. ; van Iperen, E. ; 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. ; van der Schouw, Y. T. ; Matullo, G. ; Fiorito, G. ; Guarrera, S. ; Sacerdote, C. ; Wareham, N. J. ; Langenberg, C. ; Scott, R. A. ; Luan, J. ; Bobak, M. ; Malyutina, S. ; Pająk, 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. ; de Andrade, M. ; 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. ; van der Harst, P. ; Said, M. A. ; Eppinga, R. N. ; Verweij, N. ; Snieder, H. ; authors, L. C. (Collaboration Author) ; Christen, T. ; Mook-Kanamori, D. O. ; Consortium, I. (Collaboration Author) ; Gustafsson, S. ; Lind, L. ; Ingelsson, E. ; Pazoki, R. ; Franco, O. ; Hofman, A. ; Uitterlinden, A. ; Dehghan, A. ; Teumer, A. ; Baumeister, S. ; Dörr, M. ; Lerch, M. M. ; Völker, U. ; Völzke, 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. ; Kumari, M. ; Mahajan, A. ; Hopewell, J. C. ; Seshadri, S. ; ISGC, M. C. o. t. (Collaboration Author) ; 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.DKFZ* ; 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.

2019
BioMed Central London

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Please use a persistent id in citations: doi:10.1186/s12872-019-1187-z

Abstract: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.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.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.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.

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Contributing Institute(s):

1. C020 Epidemiologie von Krebs (C020)

Research Program(s):

1. 323 - Metabolic Dysfunction as Risk Factor (POF3-323) (POF3-323)

Appears in the scientific report 2019

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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