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

Gregson, J. M. et al. (2017) Genetic invalidation of Lp-PLA2 as a therapeutic target: large-scale study of five functional Lp-PLA2-lowering alleles. European Journal of Preventive Cardiology, 24(5), pp. 492-504. (doi: 10.1177/2047487316682186) (PMID:27940953)

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.

• Item Type: Articles
• Additional Information: The work of the coordinating centre was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), British Heart Foundation Cambridge Cardiovascular Centre of Excellence, UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834), European Commission Framework Programme 7 (HEALTH-F2-2012-279233).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Caslake, Professor Muriel and Ford, Professor Ian and Packard, Professor Chris and Sattar, Professor Naveed
• Authors: Gregson, J. M., Freitag, D. F., Surendran, P., Stitziel, N. O., Chowdhury, R., Burgess, S., Kaptoge, S., Gao, P., Staley, J. R., Willeit, P., Nielsen, S. F., Caslake, M., Trompet, S., Polfus, L. M., Kuulasmaa, K., Kontto, J., Perola, M., Blankenberg, S., Veronesi, G., Gianfagna, F., Männistö, S., Kimura, A., Lin, H., Reilly, D. F., Gorski, M., Mijatovic, V., Munroe, P. B., Ehret, G. B., Thompson, A., Uria-Nickelsen, M., Malarstig, A., Dehghan, A., Vogt, T. F., Sasaoka, T., Takeuchi, F., Kato, N., Yamada, Y., Kee, F., Müller-Nurasyid, M., Ferrières, J., Arveiler, D., Amouyel, P., Salomaa, V., Boerwinkle, E., Thompson, S. G., Ford, I., Jukema, J. W., Sattar, N., Packard, C. J., Majumder, A. a. S., Alam, D. S., Deloukas, P., Schunkert, H., Samani, N. J., Kathiresan, S., Nordestgaard, B. G., Saleheen, D., Howson, J. M.M., Di Angelantonio, E., Butterworth, A. S., and Danesh, J.
• Subjects: R Medicine > R Medicine (General)
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: European Journal of Preventive Cardiology
• Publisher: SAGE Publications
• ISSN: 2047-4873
• ISSN (Online): 2047-4881
• Published Online: 11 December 2016
• Copyright Holders: Copyright © 2016 The European Society of Cardiology
• First Published: First published in European Journal of Preventive Cardiology 24(5): 492-504
• Publisher Policy: Reproduced in accordance with the publisher copyright policy