Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles
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Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles. / 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; CKDGen Consortium.
in: EUR J PREV CARDIOL, Jahrgang 24, Nr. 5, 03.2017, S. 492-504.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Review › Forschung
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T1 - Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles
AU - Gregson, John M
AU - Freitag, Daniel F
AU - Surendran, Praveen
AU - Stitziel, Nathan O
AU - Chowdhury, Rajiv
AU - Burgess, Stephen
AU - Kaptoge, Stephen
AU - Gao, Pei
AU - Staley, James R
AU - Willeit, Peter
AU - Nielsen, Sune F
AU - Caslake, Muriel
AU - Trompet, Stella
AU - Polfus, Linda M
AU - Kuulasmaa, Kari
AU - Kontto, Jukka
AU - Perola, Markus
AU - Blankenberg, Stefan
AU - Veronesi, Giovanni
AU - Gianfagna, Francesco
AU - Männistö, Satu
AU - Kimura, Akinori
AU - Lin, Honghuang
AU - Reilly, Dermot F
AU - Gorski, Mathias
AU - Mijatovic, Vladan
AU - Munroe, Patricia B
AU - Ehret, Georg B
AU - Thompson, Alex
AU - Uria-Nickelsen, Maria
AU - Malarstig, Anders
AU - Dehghan, Abbas
AU - Vogt, Thomas F
AU - Sasaoka, Taishi
AU - Takeuchi, Fumihiko
AU - Kato, Norihiro
AU - Yamada, Yoshiji
AU - Kee, Frank
AU - Müller-Nurasyid, Martina
AU - Ferrières, Jean
AU - Arveiler, Dominique
AU - Amouyel, Philippe
AU - Salomaa, Veikko
AU - Boerwinkle, Eric
AU - Thompson, Simon G
AU - Ford, Ian
AU - Wouter Jukema, J
AU - Sattar, Naveed
AU - Packard, Chris J
AU - Shafi Majumder, Abdulla Al
AU - Alam, Dewan S
AU - Deloukas, Panos
AU - Schunkert, Heribert
AU - Samani, Nilesh J
AU - Kathiresan, Sekar
AU - Nordestgaard, Børge G
AU - Saleheen, Danish
AU - Howson, Joanna Mm
AU - Di Angelantonio, Emanuele
AU - Butterworth, Adam S
AU - Danesh, John
AU - CKDGen Consortium
PY - 2017/3
Y1 - 2017/3
N2 - 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.
AB - 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.
KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase/drug effects
KW - Adult
KW - Aged
KW - Alleles
KW - Benzaldehydes/therapeutic use
KW - Case-Control Studies
KW - Coronary Disease/diagnosis
KW - Female
KW - Gene Expression Regulation
KW - Genotype
KW - Humans
KW - Male
KW - Middle Aged
KW - Molecular Targeted Therapy
KW - Oximes/therapeutic use
KW - Phospholipase A2 Inhibitors/therapeutic use
KW - Polymorphism, Single Nucleotide
KW - Randomized Controlled Trials as Topic
KW - Reference Values
KW - Reproducibility of Results
KW - Risk Assessment
KW - Treatment Outcome
U2 - 10.1177/2047487316682186
DO - 10.1177/2047487316682186
M3 - SCORING: Review article
C2 - 27940953
VL - 24
SP - 492
EP - 504
JO - EUR J PREV CARDIOL
JF - EUR J PREV CARDIOL
SN - 2047-4873
IS - 5
ER -