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Genetic invalidation of Lp-PLA as a therapeutic target: Large-scale study of five functional Lp-PLA-lowering alleles.

TitleGenetic invalidation of Lp-PLA as a therapeutic target: Large-scale study of five functional Lp-PLA-lowering alleles.
Publication TypeJournal Article
Year of Publication2017
AuthorsGregson JM, Freitag DF, Surendran P, Stitziel NO, Chowdhury, iv 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, Männisto S, Kimura A, Lin H, Reilly DF, Gorski M, Mijatovic V, Munroe PB, Ehret GB, Thompson A, Uria-Nickelsen M, Malarstig A, Dehghan A, 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, J Jukema W, Sattar N, Packard CJ, Majumder AAl Shafi, Alam DS, Deloukas P, Schunkert H, Samani NJ, Kathiresan S, Nordestgaard BG, Saleheen D, Howson JMm, Di Angelantonio E, Butterworth AS
Secondary AuthorsDanesh J
Corporate AuthorsCKDGen Consortium, International Consortium for Blood Pressure, CHARGE Inflammation working group, MICAD Exome consortium, EPIC-CVD consortium and the CHD Exome+ consortium
JournalEur J Prev Cardiol
Date Published2017 03
Keywords1-Alkyl-2-acetylglycerophosphocholine Esterase, Adult, Aged, Alleles, Benzaldehydes, Case-Control Studies, Coronary Disease, Female, Gene Expression Regulation, Genotype, Humans, Male, Middle Aged, Molecular Targeted Therapy, Oximes, Phospholipase A2 Inhibitors, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Reference Values, Reproducibility of Results, Risk Assessment, Treatment Outcome

Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A (Lp-PLA), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA 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-PLA. 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 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA-lowering alleles. Results Lp-PLA activity was decreased by 64% ( p = 2.4 × 10) with carriage of any of the four loss-of-function variants, by 45% ( p 

Alternate JournalEur J Prev Cardiol
PubMed ID27940953
PubMed Central IDPMC5460752
Grant ListSP/09/002 / BHF_ / British Heart Foundation / United Kingdom
MC_UU_00002/7 / MRC_ / Medical Research Council / United Kingdom
268834 / ERC_ / European Research Council / International
RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom
G0800270 / MRC_ / Medical Research Council / United Kingdom