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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. ; Ferrieres, J.* ; Arveiler, D.* ; Amouyel, P.* ; Salomaa, V.* ; Boerwinkle, E.* ; Thompson, S.G.* ; Ford, I.* ; Jukema, J.W.* ; Sattar, N.* ; Packard, C.J.* ; Al Shafi Majumder, A.* ; Alam, D.S.* ; Deloukas, P.* ; Schunkert, H.* ; Samani, N.J.* ; Kathiresan, S.* ; Nørdestgaard, B.G.* ; Saleheen, D.* ; Howson, J.M.M.* ; di Angelantonio, E.* ; Butterworth, A.S.* ; Danesh, J.*

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

Eur. J. Prev. Cardiol. 24, 492-504 (2017)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Human genetics; coronary heart disease; darapladib; lipoprotein-associated phospholipase A2; target validation
ISSN (print) / ISBN 2047-4873
e-ISSN 2047-4881
Journal European Journal of Preventive Cardiology
Quellenangaben Volume: 24, Issue: 5, Pages: 492-504 Article Number: , Supplement: ,
Publisher Sage
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)