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Gregson, John M.; Freitag, Daniel F.; Surendran, Praveen; Stitziel, Nathan O.; Chowdhury, Rajiv; Burgess, Stephen; Kaptoge, Stephen; Gao, Pei; Staley, James R.; Willeit, Peter; Nielsen, Sune F.; Caslake, Muriel; Trompet, Stella; Polfus, Linda M.; Kuulasmaa, Kari; Kontto, Jukka; Perola, Markus; Blankenberg, Stefan; Veronesi, Giovanni; Gianfagna, Francesco; Männistö, Satu; Kimura, Akinori; Lin, Honghuang; Reilly, Dermot F.; Gorski, Mathias; Mijatovic, Vladan; Munroe, Patricia B.; Ehret, Georg B.; Thompson, Alex; Uria-Nickelsen, Maria; Malarstig, Anders; Dehghan, Abbas; Vogt, Thomas F.; Sasaoka, Taishi; Takeuchi, Fumihiko; Kato, Norihiro; Yamada, Yoshiji; Kee, Frank; Müller-Nurasyid, Martina; Ferrières, Jean; Arveiler, Dominique; Amouyel, Philippe; Salomaa, Veikko; Boerwinkle, Eric; Thompson, Simon G.; Ford, Ian; Jukema, J. Wouter; Sattar, Naveed; Packard, Chris J.; Majumder, Abdulla al Shafi; Alam, Dewan S.; Deloukas, Panos; Schunkert, Heribert; Samani, Nilesh J.; Kathiresan, Sekar; Nordestgaard, Borge G.; Saleheen, Danish; Howson, Joanna M. M.; Angelantonio, Emanuele di; Butterworth, Adam S. and Danesh, John (2017): Genetic invalidation of Lp-PLA₂ as a therapeutic target: Large-scale study of five functional Lp-PLA₂-lowering alleles. In: European Journal of Preventive Cardiology, Vol. 24, No. 5: pp. 492-504 [PDF, 292kB]


Aims: Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA(2) 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(2). 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(2) activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA(2)-lowering alleles. Results: Lp-PLA(2) activity was decreased by 64% (p = 2.4 x 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 x 10 (-12)) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA(2) activity by 65% (p< 10 (-300)). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA(2) 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(2)-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA(2) is unlikely to be a causal risk factor.

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