Gregson, John M. and Freitag, Daniel F. and Surendran, Praveen and Stitziel, Nathan O. and Chowdhury, Rajiv and Burgess, Stephen and Kaptoge, Stephen and Gao, Pei and Staley, James R. and Willeit, Peter and Nielsen, Sune F. and Caslake, Muriel and Trompet, Stella and Polfus, Linda M. and Kuulasmaa, Kari and Kontto, Jukka and Perola, Markus and Blankenberg, Stefan and Veronesi, Giovanni and Gianfagna, Francesco and Mannisto, Satu and Kimura, Akinori and Lin, Honghuang and Reilly, Dermot F. and Gorski, Mathias and Mijatovic, Vladan and Munroe, Patricia B. and Ehret, Georg B. and Thompson, Alex and Uria-Nickelsen, Maria and Malarstig, Anders and Dehghan, Abbas and Vogt, Thomas F. and Sasaoka, Taishi and Takeuchi, Fumihiko and Kato, Norihiro and Yamada, Yoshiji and Kee, Frank and Mueller-Nurasyid, Martina and Ferrieres, Jean and Arveiler, Dominique and Amouyel, Philippe and Salomaa, Veikko and Boerwinkle, Eric and Thompson, Simon G. and Ford, Ian and Jukema, J. Wouter and Sattar, Naveed and Packard, Chris J. and Majumder, Abdulla al Shafi and Alam, Dewan S. and Deloukas, Panos and Schunkert, Heribert and Samani, Nilesh J. and Kathiresan, Sekar and Nordestgaard, Borge G. and Saleheen, Danish and Howson, Joanna M. M. and Di Angelantonio, Emanuele and Butterworth, Adam S. and Danesh, John (2017) Genetic invalidation of Lp-PLA(2) as a therapeutic target: Large-scale study of five functional Lp-PLA(2)-lowering alleles. EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY, 24 (5). pp. 492-504. ISSN 2047-4873, 2047-4881
Full text not available from this repository. (Request a copy)Abstract
Aims: Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA(2) 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-PLA(2). 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-PLA(2) activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA(2)-lowering alleles. Results: Lp-PLA(2) activity was decreased by 64% (p = 2.4 x 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 x 10 (-12)) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA(2) activity by 65% (p< 10 (-300)). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA(2) 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-PLA(2)-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA(2) is unlikely to be a causal risk factor.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CORONARY-HEART-DISEASE; ACTIVATING-FACTOR ACETYLHYDROLASE; PHOSPHOLIPASE A(2) ACTIVITY; GENOME-WIDE ASSOCIATION; CARDIOVASCULAR-DISEASE; ARTERY-DISEASE; RISK; DARAPLADIB; VARIANTS; EVENTS; Human genetics; target validation; coronary heart disease; lipoprotein-associated phospholipase A(2); darapladib |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Nephrologie Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:01 |
| Last Modified: | 20 Feb 2019 11:13 |
| URI: | https://pred.uni-regensburg.de/id/eprint/299 |
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