Gianfagna F

References (1)

Title : Genetic invalidation of Lp-PLA(2) as a therapeutic target: Large-scale study of five functional Lp-PLA(2)-lowering alleles - Gregson_2017_Eur.J.Prev.Cardiol_24_492
Author(s) : Gregson 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 , Mannisto S , Kimura A , Lin H , Reilly DF , Gorski M , Mijatovic V , Munroe PB , Ehret GB , Thompson A , Uria-Nickelsen M , Malarstig A , Dehghan A , Vogt TF , Sasaoka T , Takeuchi F , Kato N , Yamada Y , Kee F , Muller-Nurasyid M , Ferrieres 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 , Nordestgaard BG , Saleheen D , Howson JM , Di Angelantonio E , Butterworth AS , Danesh J
Ref : Eur J Prev Cardiol , 24 :492 , 2017
Abstract : 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.
ESTHER : Gregson_2017_Eur.J.Prev.Cardiol_24_492
PubMedSearch : Gregson_2017_Eur.J.Prev.Cardiol_24_492
PubMedID: 27940953
Gene_locus related to this paper: human-PLA2G7