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

John M. Gregson, Daniel F. Freitag, Praveen Surendran, Nathan O. Stitziel, Rajiv Chowdhury, Stephen Burgess, Stephen Kaptoge, Pei Gao, James R. Staley, Peter Willeit, Sune F. Nielsen, Muriel Caslake, Stella Trompet, Linda M. Polfus, Kari Kuulasmaa, Jukka Kontto, Markus Perola, Stefan Blankenberg, Giovanni Veronesi, Francesco GianfagnaSatu Männistö, Akinori Kimura, Honghuang Lin, Dermot F. Reilly, Mathias Gorski, Vladan Mijatovic, Patricia B. Munroe, Georg B. Ehret, Alex Thompson, Maria Uria-Nickelsen, Anders Malarstig, Abbas Dehghan, Thomas F. Vogt, Taishi Sasaoka, Fumihiko Takeuchi, Norihiro Kato, Yoshiji Yamada, Frank Kee, Martina Müller-Nurasyid, Jean Ferrières, Dominique Arveiler, Philippe Amouyel, Veikko Salomaa, Eric Boerwinkle, Simon G. Thompson, Ian Ford, J. Wouter Jukema, Naveed Sattar, Chris J. Packard, Abdulla Al Shafi Majumder, Dewan S. Alam, Panos Deloukas, Heribert Schunkert, Nilesh J. Samani, Sekar Kathiresan, Børge G. Nordestgaard, Danish Saleheen, Joanna M.M. Howson, Emanuele Di Angelantonio, Adam S. Butterworth, John Danesh

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)492-504
Number of pages13
JournalEuropean Journal of Preventive Cardiology
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2017

Keywords

  • Human genetics
  • coronary heart disease
  • darapladib
  • lipoprotein-associated phospholipase A
  • target validation

ASJC Scopus subject areas

  • Epidemiology
  • Cardiology and Cardiovascular Medicine

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