Title |
Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles
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Published in |
European Journal of Preventive Cardiology, December 2016
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DOI | 10.1177/2047487316682186 |
Pubmed ID | |
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, the CKDGen consortium, Patricia B Munroe, Georg B Ehret, the International Consortium for Blood Pressure, Alex Thompson, Maria Uria-Nickelsen, Anders Malarstig, Abbas Dehghan, the 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, the MICAD Exome consortium, Børge G Nordestgaard, Danish Saleheen, Joanna MM Howson, Emanuele Di Angelantonio, Adam S Butterworth, John Danesh, the EPIC-CVD consortium and the CHD Exome+ consortium |
Abstract |
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. 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. 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. 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 2 | 25% |
United States | 1 | 13% |
Norway | 1 | 13% |
China | 1 | 13% |
Unknown | 3 | 38% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 4 | 50% |
Practitioners (doctors, other healthcare professionals) | 2 | 25% |
Scientists | 2 | 25% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 2 | 2% |
Qatar | 1 | 1% |
Unknown | 79 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 14 | 17% |
Student > Master | 10 | 12% |
Professor | 9 | 11% |
Student > Ph. D. Student | 6 | 7% |
Student > Bachelor | 5 | 6% |
Other | 14 | 17% |
Unknown | 24 | 29% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 23 | 28% |
Biochemistry, Genetics and Molecular Biology | 10 | 12% |
Nursing and Health Professions | 6 | 7% |
Agricultural and Biological Sciences | 2 | 2% |
Mathematics | 2 | 2% |
Other | 11 | 13% |
Unknown | 28 | 34% |