Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2 -lowering alleles.

Détails

ID Serval
serval:BIB_4856BCF7E278
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2 -lowering alleles.
Périodique
European journal of preventive cardiology
Auteur(s)
Gregson J.M., Freitag D.F., Surendran P., Stitziel N.O., Chowdhury R., Burgess S., Kaptoge S., Gao P., Staley J.R., Willeit P., Nielsen S.F., Caslake M., Trompet S., Polfus L.M., Kuulasmaa K., Kontto J., Perola M., Blankenberg S., Veronesi G., Gianfagna F., Männistö S., Kimura A., Lin H., Reilly D.F., Gorski M., Mijatovic V., Munroe P.B., Ehret G.B., Thompson A., Uria-Nickelsen M., Malarstig A., Dehghan A., Vogt T.F., Sasaoka T., Takeuchi F., Kato N., Yamada Y., Kee F., Müller-Nurasyid M., Ferrières J., Arveiler D., Amouyel P., Salomaa V., Boerwinkle E., Thompson S.G., Ford I., Wouter Jukema J., Sattar N., Packard C.J., Shafi Majumder A.A., Alam D.S., Deloukas P., Schunkert H., Samani N.J., Kathiresan S., Nordestgaard B.G., Saleheen D., Howson J.M., Di Angelantonio E., Butterworth A.S., Danesh J.
Collaborateur(s)
CKDGen consortium, International Consortium for Blood Pressure, CHARGE inflammation working group, MICAD Exome consortium, EPIC-CVD consortium and the CHD Exome+ consortium
ISSN
2047-4881 (Electronic)
ISSN-L
2047-4873
Statut éditorial
Publié
Date de publication
03/2017
Peer-reviewed
Oui
Volume
24
Numéro
5
Pages
492-504
Langue
anglais
Notes
Publication types: Journal Article ; Review
Publication Status: ppublish
Résumé
Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A javax.xml.bind.JAXBElement@3ed2b341 (Lp-PLA javax.xml.bind.JAXBElement@3d94c871 ), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA javax.xml.bind.JAXBElement@ab2bb75 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 javax.xml.bind.JAXBElement@77eb0872 . 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 javax.xml.bind.JAXBElement@5c08e575 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA javax.xml.bind.JAXBElement@474479c5 -lowering alleles. Results Lp-PLA javax.xml.bind.JAXBElement@58b21b4b activity was decreased by 64% ( p = 2.4 × 10 javax.xml.bind.JAXBElement@77b520b7 ) with carriage of any of the four loss-of-function variants, by 45% ( p < 10 javax.xml.bind.JAXBElement@6c8d5079 ) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 × 10 javax.xml.bind.JAXBElement@8e3967c ) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA javax.xml.bind.JAXBElement@4043bc68 activity by 65% ( p < 10 javax.xml.bind.JAXBElement@1ead8c4f ). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA javax.xml.bind.JAXBElement@1825097b 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-PLA javax.xml.bind.JAXBElement@c612c75 -lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA javax.xml.bind.JAXBElement@511c716d is unlikely to be a causal risk factor.

Mots-clé
1-Alkyl-2-acetylglycerophosphocholine Esterase/drug effects, 1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics, Adult, Aged, Alleles, Benzaldehydes/therapeutic use, Case-Control Studies, Coronary Disease/diagnosis, Coronary Disease/drug therapy, Coronary Disease/genetics, Female, Gene Expression Regulation, Genotype, Humans, Male, Middle Aged, Molecular Targeted Therapy, Oximes/therapeutic use, Phospholipase A2 Inhibitors/therapeutic use, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Reference Values, Reproducibility of Results, Risk Assessment, Treatment Outcome, Human genetics, coronary heart disease, darapladib, lipoprotein-associated phospholipase A2, target validation
Pubmed
Web of science
Création de la notice
22/12/2016 11:40
Dernière modification de la notice
20/08/2019 13:55
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