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

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.

doi:10.1177/2047487316682186

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

Details

Download: 27940953_BIB_4856BCF7E278.pdf (293.81 [Ko])
State: Public
Version: Final published version
License: CC BY 4.0

Serval ID

serval:BIB_4856BCF7E278

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

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

Journal

European journal of preventive cardiology

Author(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.

Working group(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

Publication state

Published

Issued date

03/2017

Peer-reviewed

Oui

Volume

Number

Pages

492-504

Language

english

Notes

Publication types: Journal Article ; Review
Publication Status: ppublish

Abstract

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.

Keywords

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

URN

urn:nbn:ch:serval-BIB_4856BCF7E2789

OAI-PMH

oai:serval.unil.ch:BIB_4856BCF7E278

DOI

10.1177/2047487316682186

Pubmed

27940953

Web of science

000397434800006

Create date

22/12/2016 11:40