| Title: |
Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. |
| Authors: |
Schmidt, AF; Holmes, MV; Preiss, D; Swerdlow, DI; Denaxas, S; Fatemifar, G; Faraway, R; Finan, C; Valentine, D; Fairhurst-Hunter, Z; Hartwig, FP; Horta, BL; Hypponen, E; Power, C; Moldovan, M; van Iperen, E; Hovingh, K; Demuth, I; Norman, K; Steinhagen-Thiessen, E; Demuth, J; Bertram, L; Lill, CM; Coassin, S; Willeit, J; Kiechl, S; Willeit, K; Mason, D; Wright, J; Morris, R; Wanamethee, G; Whincup, P; Ben-Shlomo, Y; McLachlan, S; Price, JF; Kivimaki, M; Welch, C; Sanchez-Galvez, A; Marques-Vidal, P; Nicolaides, A; Panayiotou, AG; Onland-Moret, NC; van der Schouw, YT; Matullo, G; Fiorito, G; Guarrera, S; Sacerdote, C; Wareham, NJ; Langenberg, C; Scott, RA; 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, SE; Brilliant, M; Kitchner, T; Hakonarson, H; Carrell, DS; McCarty, CA; Lester, KH; Larson, EB; Crosslin, DR; de Andrade, M; Roden, DM; Denny, JC; 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, MA; Eppinga, RN; Verweij, N; Snieder, H; Lifelines Cohort authors; Christen, T; Mook-Kanamori, DO; ICBP Consortium; Gustafsson, S; Lind, L; Ingelsson, E; Pazoki, R; Franco, O; Hofman, A; Uitterlinden, A; Dehghan, A; Teumer, A; Baumeister, S; Dörr, M; Lerch, MM; Völker, U; Völzke, H; Ward, J; Pell, JP; Meade, T; Christophersen, IE; Maitland-van der Zee, AH; Baranova, EV; Young, R; Ford, I; Campbell, A; Padmanabhan, S; Bots, ML; Grobbee, DE; Froguel, P; Thuillier, D; Roussel, R; Bonnefond, A; Cariou, B; Smart, M; Bao, Y; Kumari, M; Mahajan, A; Hopewell, JC; Seshadri, S; METASTROKE Consortium of the ISGC; Dale, C; Costa, RPE; Ridker, PM; Chasman, DI; Reiner, AP; Ritchie, MD; Lange, LA; Cornish, AJ; Dobbins, SE; 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, FW; Patel, RS; Keating, BJ; Sattar, N; Houlston, R; Casas, JP; Hingorani, AD |
| Contributors: |
Cornish, Alexander; Kinnersley, Benjamin; Law, Philip; Went, Molly; Sud, Amit; Houlston, Richard |
| Publisher Information: |
BMC |
| Publication Year: |
2020 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Subject Terms: |
Lifelines Cohort authors; ICBP Consortium; METASTROKE Consortium of the ISGC; Humans; Brain Ischemia; Myocardial Infarction; Anticholesteremic Agents; Serine Proteinase Inhibitors; Treatment Outcome; Risk Assessment; Risk Factors; Down-Regulation; Polymorphism; Single Nucleotide; Dyslipidemias; Cholesterol; LDL; Randomized Controlled Trials as Topic; Stroke; Genome-Wide Association Study; Biomarkers; Proprotein Convertase 9 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Electronic; ?; application/pdf |
| Language: |
English |
| ISSN: |
1471-2261 |
| Relation: |
BMC cardiovascular disorders, 2019, 19 (1), pp. 240 - ?; https://repository.icr.ac.uk/handle/internal/3521 |
| Availability: |
https://repository.icr.ac.uk/handle/internal/3521 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.19571893 |
| Database: |
BASE |