Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles. (March 2017)

• Record Type: Journal Article
• Authors: 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; Wouter Jukema, J; Sattar, Naveed; Packard, Chris J; Shafi Majumder, Abdulla al; Alam, Dewan S; Deloukas, Panos; Schunkert, Heribert; Samani, Nilesh J; Kathiresan, Sekar; Nordestgaard, Børge G; Saleheen, Danish; Howson, Joanna MM; Di Angelantonio, Emanuele; Butterworth, Adam S; Danesh, John;
• Is Part Of: European journal of preventive cardiology. Volume 24:Number 5(2017)
• Page Start: 492
• Page End: 504
• Publication Date: 2017-03
• Subjects: Human genetics -- target validation -- coronary heart disease -- lipoprotein-associated phospholipase A2 -- darapladib; Cardiovascular system -- Diseases -- Prevention -- Periodicals; Cardiac patients -- Rehabilitation -- Periodicals; 616.12
• DOI: 10.1177/2047487316682186
• Languages: English
• ISSNs: 2047-4873

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.