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

CollaborationWith : Ehret, Georg Benedikt
Published in European Journal of Preventive Cardiology. 2017, vol. 24, no. 5, p. 492-504
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.
Keywords 1-Alkyl-2-acetylglycerophosphocholine Esterase/drug effects/geneticsAdultAgedAllelesBenzaldehydes/therapeutic useCase-Control StudiesCoronary Disease/diagnosis/drug therapy/geneticsFemaleGene Expression RegulationGenotypeHumansMaleMiddle AgedMolecular Targeted TherapyOximes/therapeutic usePhospholipase A2 Inhibitors/therapeutic usePolymorphismSingle NucleotideRandomized Controlled Trials as TopicReference ValuesReproducibility of ResultsRisk AssessmentTreatment Outcome
PMID: 27940953
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Research group Traits génétiques complexes (901)
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EPIC-CVD CONSORTIUM AND THE CHD EXOME+ CONSORTIUM. Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles. In: European Journal of Preventive Cardiology, 2017, vol. 24, n° 5, p. 492-504. doi: 10.1177/2047487316682186 https://archive-ouverte.unige.ch/unige:128976

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Deposited on : 2020-01-15

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