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

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.

SUBMITTER: Gregson JM

PROVIDER: S-EPMC5460752 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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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 JM Freitag Daniel F DF Surendran Praveen P Stitziel Nathan O NO Chowdhury Rajiv R Burgess Stephen S Kaptoge Stephen S Gao Pei P Staley James R JR Willeit Peter P Nielsen Sune F SF Caslake Muriel M Trompet Stella S Polfus Linda M LM Kuulasmaa Kari K Kontto Jukka J Perola Markus M Blankenberg Stefan S Veronesi Giovanni G Gianfagna Francesco F Männistö Satu S Kimura Akinori A Lin Honghuang H Reilly Dermot F DF Gorski Mathias M Mijatovic Vladan V Munroe Patricia B PB Ehret Georg B GB Thompson Alex A Uria-Nickelsen Maria M Malarstig Anders A Dehghan Abbas A Vogt Thomas F TF Sasaoka Taishi T Takeuchi Fumihiko F Kato Norihiro N Yamada Yoshiji Y Kee Frank F Müller-Nurasyid Martina M Ferrières Jean J Arveiler Dominique D Amouyel Philippe P Salomaa Veikko V Boerwinkle Eric E Thompson Simon G SG Ford Ian I Wouter Jukema J J Sattar Naveed N Packard Chris J CJ Shafi Majumder Abdulla Al AA Alam Dewan S DS Deloukas Panos P Schunkert Heribert H Samani Nilesh J NJ Kathiresan Sekar S Nordestgaard Børge G BG Saleheen Danish D Howson Joanna Mm JM Di Angelantonio Emanuele E Butterworth Adam S AS Danesh John J

European journal of preventive cardiology 20161208 5

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 > ...[more]

PMID: 27940953

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Project description:PurposeGSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), which was in development as a potential treatment for Alzheimer's disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, [18F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study.Procedures[18F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [18F]trifluoromethylation methodology. Healthy male subjects (n = 4, age range 34-42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of [18F]GSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 μg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (VT). Secondary PK and safety endpoints were also recorded.ResultsPET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of [18F]GSK2647544 across all the ROIs examined. The mean whole brain VT was 0.56 (95 % CI, 0.41-0.72). Secondary PK parameters, Cmax (geometric mean) and Tmax (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20-40 % of the parent compound [18F]GSK2647544 present after 120 min.ConclusionsThe study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA2 activity.Trial registrationClintrials.gov: NCT01924858.

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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-PLA<sub>2</sub> as a therapeutic target: Large-scale study of five functional Lp-PLA<sub>2</sub>-lowering alleles.

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