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.

• Authors: 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, CKDGen consortium, Patricia B Munroe, Georg B Ehret, International Consortium for Blood Pressure, Alex Thompson, Maria Uria-Nickelsen, Anders Malarstig, Abbas Dehghan, CHARGE inflammation working group, 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, MICAD Exome consortium, Børge G Nordestgaard, Danish Saleheen, Joanna Mm Howson, Emanuele Di Angelantonio, Adam S Butterworth, John Danesh, EPIC-CVD consortium and the CHD Exome+ consortium
• Journal: European journal of preventive cardiology (Eur J Prev Cardiol) Vol. 24 Issue 5 Pg. 492-504 (03 2017) ISSN: 2047-4881 [Electronic] England
• PMID: 27940953 (Publication Type: Journal Article, Review, Systematic Review)

Chemical References

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

Topics

• 1-Alkyl-2-acetylglycerophosphocholine Esterase (drug effects, genetics)
• Adult
• Aged
• Alleles
• Benzaldehydes (therapeutic use)
• Case-Control Studies
• Coronary Disease (diagnosis, drug therapy, 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