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

Eur J Prev Cardiol. 2017 Mar;24(5):492-504. doi: 10.1177/2047487316682186. Epub 2016 Dec 8.

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: Human genetics; coronary heart disease; darapladib; lipoprotein-associated phospholipase A2; target validation.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / drug effects
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • Adult
  • Aged
  • Alleles
  • Benzaldehydes / therapeutic use*
  • Case-Control Studies
  • Coronary Disease / diagnosis
  • Coronary Disease / drug therapy*
  • Coronary Disease / genetics*
  • Female
  • Gene Expression Regulation
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Molecular Targeted Therapy*
  • Oximes / therapeutic use*
  • Phospholipase A2 Inhibitors / therapeutic use*
  • Polymorphism, Single Nucleotide
  • Randomized Controlled Trials as Topic
  • Reference Values
  • Reproducibility of Results
  • Risk Assessment
  • Treatment Outcome

Substances

  • Benzaldehydes
  • Oximes
  • Phospholipase A2 Inhibitors
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • darapladib