Dokumentenart: | Artikel | ||||
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Titel eines Journals oder einer Zeitschrift: | European Journal of Preventive Cardiology | ||||
Verlag: | SAGE PUBLICATIONS LTD | ||||
Ort der Veröffentlichung: | LONDON | ||||
Band: | 24 | ||||
Nummer des Zeitschriftenheftes oder des Kapitels: | 5 | ||||
Seitenbereich: | S. 492-504 | ||||
Datum: | 2017 | ||||
Institutionen: | Medizin > Abteilung für Nephrologie Medizin > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie | ||||
Identifikationsnummer: |
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Stichwörter / 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 | ||||
Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
Status: | Veröffentlicht | ||||
Begutachtet: | Ja, diese Version wurde begutachtet | ||||
An der Universität Regensburg entstanden: | Ja | ||||
Dokumenten-ID: | 38638 |
Zusammenfassung
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 ...
Zusammenfassung
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.
Metadaten zuletzt geändert: 15 Jul 2021 08:16