Genetic invalidation of Lp-PLA(2) as a therapeutic target: Large-scale study of five functional Lp-PLA(2)-lowering alleles

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 pa...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2016
Materias:
Coronary Heart Disease
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460752/
https://www.ncbi.nlm.nih.gov/pubmed/27940953
http://dx.doi.org/10.1177/2047487316682186
Descripción
Sumario: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 × 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-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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