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|Title:||Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles|
|Authors:||Gregson, J. M.|
Freitag, D. F.
Stitziel, N. O.
Staley, J. R.
Nielsen, S. F.
Polfus, L. M.
Reilly, D. F.
Munroe, P. B.
Ehret, G. B.
International Consortium for Blood Pressure
CHARGE inflammation working group
Vogt, T. F.
Thompson, S. G.
Wouter Jukema, J.
Packard, C. J.
Shafi Majumder, A. A.
Alam, D. S.
Samani, Nilesh J.
MICAD Exome consortium
Nordestgaard, B. G.
Howson, J. M.
Di Angelantonio, E.
Butterworth, A. S.
EPIC-CVD consortium and the CHD Exome+ consortium
|Publisher:||SAGE Publications for The European Society of Cardiology|
|Citation:||European Journal of Preventive Cardiology, 2017, 24 (5), pp. 492-504|
|Abstract:||Aims: Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2 enzyme activity is causally relevant to coronary heart disease. 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-PLA2. 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-PLA2 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles. Results: Lp-PLA2 activity was decreased by 64% ( p = 2.4 × 10(-25)) with carriage of any of the four loss-of-function variants, by 45% ( p < 10(-300)) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 × 10(-12)) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA2 activity by 65% ( p < 10(-300)). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2 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. Conclusions: In a large-scale human genetic study, none of a series of Lp-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2 is unlikely to be a causal risk factor.|
|Rights:||Copyright © the authors, 2016. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
|Appears in Collections:||Published Articles, Dept. of Cardiovascular Sciences|
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