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

  • John M Gregson
  • Daniel F Freitag
  • Praveen Surendran
  • Nathan O Stitziel
  • Rajiv Chowdhury
  • Stephen Burgess
  • Stephen Kaptoge
  • Pei Gao
  • James R Staley
  • Peter Willeit
  • Sune F Nielsen
  • Muriel Caslake
  • Stella Trompet
  • Linda M Polfus
  • Kari Kuulasmaa
  • Jukka Kontto
  • Markus Perola
  • Stefan Blankenberg
  • Giovanni Veronesi
  • Francesco Gianfagna
  • Satu Männistö
  • Akinori Kimura
  • Honghuang Lin
  • Dermot F Reilly
  • Mathias Gorski
  • Vladan Mijatovic
  • Patricia B Munroe
  • Georg B Ehret
  • Alex Thompson
  • Maria Uria-Nickelsen
  • Anders Malarstig
  • Abbas Dehghan
  • Thomas F Vogt
  • Taishi Sasaoka
  • Fumihiko Takeuchi
  • Norihiro Kato
  • Yoshiji Yamada
  • Frank Kee
  • Martina Müller-Nurasyid
  • Jean Ferrières
  • Dominique Arveiler
  • Philippe Amouyel
  • Veikko Salomaa
  • Eric Boerwinkle
  • Simon G Thompson
  • Ian Ford
  • J Wouter Jukema
  • Naveed Sattar
  • Chris J Packard
  • Abdulla Al Shafi Majumder
  • Dewan S Alam
  • Panos Deloukas
  • Heribert Schunkert
  • Nilesh J Samani
  • Sekar Kathiresan
  • Børge G Nordestgaard
  • Danish Saleheen
  • Joanna Mm Howson
  • Emanuele Di Angelantonio
  • Adam S Butterworth
  • John Danesh
  • CKDGen consortium

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.

Bibliographical metadata

Original languageEnglish
ISSN2047-4873
DOIs
Publication statusPublished - 03.2017
PubMed 27940953