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; Demuth, Juri; Bertram, Lars; Lill, Christina M.; Coassin, Stefan; Willeit, Johann; Kiechl, Stefan; Willeit, Karin; Mason, Dan; Wright, John; Morris, Richard; Wanamethee, Goya; Whincup, Peter; Ben-Shlomo, Yoav; McLachlan, Stela; Price, Jackie F.; Kivimaki, Mika; Welch, Catherine; Sanchez-Galvez, Adelaida; Marques-Vidal, Pedro; Nicolaides, Andrew; Panayiotou, Andrie G.; Onland-Moret, N. Charlotte; Van Der Schouw, Yvonne T.; Matullo, Giuseppe; Fiorito, Giovanni; Guarrera, Simonetta; Sacerdote, Carlotta; Wareham, Nicholas J.; Langenberg, Claudia; Scott, Robert A.; Luan, Jian'An; Bobak, Martin; Malyutina, Sofia; Pajak, Andrzej; Kubinova, Ruzena; Tamosiunas, Abdonas; Pikhart, Hynek; Grarup, Niels; Pedersen, Oluf; Hansen, Torben; Linneberg, Allan; Jess, Tine; Cooper, Jackie; Humphries, Steve E.; Brilliant, Murray; Kitchner, Terrie; Hakonarson, Hakon; Carrell, David S.; McCarty, Catherine A.; Lester, Kirchner H.; Larson, Eric B.; Crosslin, David R.; De Andrade, Mariza; Roden, Dan M.; Denny, Joshua C.; Carty, Cara; Hancock, Stephen; Attia, John; Holliday, Elizabeth; Scott, Rodney; Schofield, Peter; O'Donnell, Martin; Yusuf, Salim; Chong, Michael; Pare, Guillaume; Van Der Harst, Pim; Said, M. Abdullah; Eppinga, Ruben N.; Verweij, Niek; Snieder, Harold; Christen, Tim; Mook-Kanamori, D. O.; Gustafsson, Stefan; Lind, Lars; Ingelsson, Erik; Pazoki, Raha; Franco, Oscar; Hofman, Albert; Uitterlinden, Andre; Dehghan, Abbas; Teumer, Alexander; Baumeister, Sebastian; Dörr, Marcus; Lerch, Markus M.; Völker, Uwe; Völzke, Henry; Ward, Joey; Pell, Jill P.; Meade, Tom; Christophersen, Ingrid E.; Maitland-Van Der Zee, Anke H.; Baranova, Ekaterina V.; Young, Robin; Ford, Ian; Campbell, Archie; Padmanabhan, Sandosh; Bots, Michiel L.; Grobbee, Diederick E.; Froguel, Philippe; Thuillier, Dorothée; Roussel, Ronan; Bonnefond, Amélie; Cariou, Bertrand; Smart, Melissa; Bao, Yanchun; Kumari, Meena; Mahajan, Anubha; Hopewell, Jemma C.; Seshadri, Sudha; Dale, Caroline; Costa, Rui Providencia E.; Ridker, Paul M.; Chasman, Daniel I.; Reiner, Alex P.; Ritchie, Marylyn D.; Lange, Leslie A.; Cornish, Alex J.; Dobbins, Sara E.; Hemminki, Kari; Kinnersley, Ben; Sanson, Marc; Labreche, Karim; Simon, Matthias; Bondy, Melissa; Law, Philip; Speedy, Helen; Allan, James; Li, Ni; Went, Molly; Weinhold, Niels; Morgan, Gareth; Sonneveld, Pieter; Nilsson, Björn; Goldschmidt, Hartmut; Sud, Amit; Engert, Andreas; Hansson, Markus; Hemingway, Harry; Asselbergs, Folkert W.; Patel, Riyaz S.; Keating, Brendan J.; Sattar, Naveed; Houlston, Richard; Casas, Juan P.; Hingorani, Aroon D.
(2019) BMC Cardiovascular Disorders, volume 19, issue 1
(Article)
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
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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.
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Keywords: Genetic association studies, LDL-cholesterol, Mendelian randomisation, Phenome-wide association scan, Cardiology and Cardiovascular Medicine
ISSN: 1471-2261
Publisher: BioMed Central
Note: Funding Information: Dr. Schmidt is supported by BHF grant PG/18/5033837. Dr. Preiss is supported by a University of Oxford BHF Centre of Research Excellence Senior Transition Fellowship (RE/13/1/30181). This research has been funded by the British Heart Foundation (SP/13/6/30554, RG/10/12/28456), and the UCL BHF Research Accelerator grant (AA/18/6/24223). The work was also supported by UCL Hospitals NIHR Biomedical Research Centre and by the Rosetrees and Stoneygate Trusts. This research has been conducted using the UK Biobank Resource under Application Number 12113. The authors are grateful to UK Biobank participants. UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government and the British Heart Foundation. We thank the International Genomics of Alzheimer’s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips was funded by the French National Foundation on Alzheimer’s disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer’s Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer’s Association grant ADGC–10–196728. We acknowledge the International Consortium for Blood Pressure Genome-Wide Association Studies (Nature. 2011 Sep 11;478(7367):103–9, Nat Genet. 2011 Sep 11;43(10):1005–11). This work was supported in part by Deutsche Forschungsgemeinschaft (DFG Az Si 552/2), the University of Bonn (BONFOR O-126.0030), and Deutsche Krebshilfe (70/2385/WI2, 70/3163/WI3; PI Prof. J Schramm, Dept. Bloodwise provided funding for the study (LRF05001, LRF06002 and LRF13044) with additional support from Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the Arbib Fund. Wellcome Trust [064947/Z/01/Z and 081081/Z/06/Z]; from the National Institute on Aging [1R01 AG23522–01]; and the MacArthur Foundation “MacArthur Initiative on Social Upheaval and Health” [71208]. The British Women’s Heart and Health Study is supported by the British Heart Foundation (PG/13/66/30442). Data on mortality and cancer events were routinely provided from NHS Digital to the BWHHS under data sharing agreement MR104a-Regional Heart Study (Female Cohort). British Women’s Heart and Health Study data are available to bona fide researchers for research purposes. Please refer to the BWHHS data sharing policy at www.ucl.ac.uk/british-womens-heart-health-study . Hartmut Goldschmidt acknowledges support from the Deutsche Krebshilfe, the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS (01ZX1309), Deutsche Krebshilfe, the Dietmar Hopp Foundation and the German Ministry of Education and Science (BMBF: CLIOMMICS (01ZX1309). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). This study was supported by the Farr Institute of Health Informatics Research, funded by The Medical Research Council (MR/K006584/1), in partnership with Arthritis Research UK, the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Engineering and Physical Sciences Research Council, the National Institute of Health Research, the National Institute for Social Care and Health Research (Welsh Assembly Government), the Chief Scientist Office (Scottish Government Health Directorates) and the Wellcome Trust. Christina M Lill is supported by the Possehl foundation, Renate Maaß Foundation. Mika Kivimaki was supported by MRC (K013351 and R024227) and a Helsinki Institute of Life Science fellowship. Michael Holmes is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. Dr. Patel is supported by a BHF clinical intermediate fellowship (FS/14/76/30933). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Lifelines Cohort authors see Additional file 2. Publisher Copyright: © 2019 The Author(s).
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