Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles.
European Journal of Preventive Cardiology
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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.
AuthorsGregson, JM; Freitag, DF; Surendran, P; Stitziel, NO; Chowdhury, 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; Männistö, S; Kimura, A; Lin, H; Reilly, DF; Gorski, M; Mijatovic, V; CKDGen consortium; Munroe, PB; Ehret, GB; International Consortium for Blood Pressure; Thompson, A; Uria-Nickelsen, M; Malarstig, A; Dehghan, A; CHARGE inflammation working group; 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; Wouter Jukema, J; Sattar, N; Packard, CJ; Shafi Majumder, AA; Alam, DS; Deloukas, P; Schunkert, H; Samani, NJ; Kathiresan, S; MICAD Exome consortium; Nordestgaard, BG; Saleheen, D; Howson, JM; Di Angelantonio, E; Butterworth, AS; Danesh, J; EPIC-CVD consortium and the CHD Exome+ consortium
- Cardiovascular 
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