| Title: |
Genetic invalidation of Lp-PLA$_{2}$ as a therapeutic target: Large-scale study of five functional Lp-PLA$_{2}$-lowering alleles |
| Authors: |
Gregson, JM; Freitag, DF; Surendran, P; Stitziel, NO; Chowdhury, R; Burgess, S; Kaptoge, S; Gao, P; Staley, JR; Willeit, P; Nielsen, SF; Caslake, M; Trompet, S; Polfus, LM; Kuulasmaa, K; Kontto, J; Perola, M; Blankenberg, S; Veronesi, G; Gianfagna, F; Männistö, S; Kimura, A; Lin, H; Reilly, DF; Gorski, M; Mijatovic, V; CKDGen consortium; Munroe, PB; Ehret, GB; International Consortium for Blood Pressure; Thompson, A; Uria-Nickelsen, M; Malarstig, A; Dehghan, A; CHARGE inflammation working group; Vogt, TF; Sasaoka, T; Takeuchi, F; Kato, N; Yamada, Y; Kee, F; Müller-Nurasyid, M; Ferrières, J; Arveiler, D; Amouyel, P; Salomaa, V; Boerwinkle, E; Thompson, SG; Ford, I; Wouter Jukema, J; Sattar, N; Packard, CJ; Shafi Majumder, AA; Alam, DS; Deloukas, P; Schunkert, H; Samani, NJ; Kathiresan, S; MICAD Exome consortium; Nordestgaard, BG; Saleheen, D; Howson, JM; Di Angelantonio, E; Butterworth, AS; Danesh, J; EPIC-CVD consortium and the CHD Exome+ consortium |
| Publisher Information: |
SAGE Publications Ltd; //doi.org/10.1177/2047487316682186; European Journal of Preventive Cardiology |
| Publication Year: |
2017 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
human genetics; target validation; coronary heart disease; lipoprotein-associated phospholipase A2; darapladib |
| Description: |
$\textbf{Aims}$ Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A$_{2}$ (Lp-PLA$_{2}$), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA$_{2}$ enzyme activity is causally relevant to coronary heart disease. $\textbf{Methods }$ In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA$_{2}$. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA$_{2}$ activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA$_{2}$-lowering alleles. $\textbf{Results }$ Lp-PLA$_{2}$ activity was decreased by 64% ( $\textit{p}$ = 2.4 × 10$^{-25}$) with carriage of any of the four loss-of-function variants, by 45% ( $\textit{p}$ < 10$^{-300}$) for every allele inherited at Val279Phe, and by 2.7% ( $\textit{p}$ = 1.9 × 10$^{-12}$) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA$_{2}$ activity by 65% ( $\textit{p}$ < 10$^{-300}$). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA$_{2}$ activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. $\textbf{Conclusions }$ In a large-scale human genetic study, none of a series of Lp-PLA$_{2}$-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA$_{2}$ is unlikely to be ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/263172 |
| DOI: |
10.17863/CAM.8479 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/263172; https://doi.org/10.17863/CAM.8479 |
| Rights: |
All rights reserved ; http://purl.org/NET/rdflicense/allrightsreserved |
| Accession Number: |
edsbas.2D1DAD5E |
| Database: |
BASE |