"Folkersen, Lasse" . "Rothenbacher, Dietrich" . "Hub\u00E1\u010Dek, Jaroslav" . "Staines-Urias, Eleonora" . "Boer, Jolanda MA" . "US - Spojen\u00E9 st\u00E1ty americk\u00E9" . "Scholz, Markus" . "Veglia, Fabrizio" . "Breitling, Lutz P" . "Guardiola, Montse" . "Exeter, Holly J" . . "Trompet, Stella" . . "Li, Mingyao" . "http://www.sciencedirect.com/science/article/pii/S0735109713027782" . "Kotti, Salma" . "RIV/00023001:_____/13:00058759" . "Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. Background Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Conclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events. (C) 2013 by the American College of Cardiology Foundation" . "Secretory Phospholipase A(2)-IIA and Cardiovascular Disease"@en . . . "Gansevoort, Ron T" . "Stephens, Jeffrey W" . . "Hofman, Albert" . "Dallmeier, Dhayana" . "21" . "Secretory Phospholipase A(2)-IIA and Cardiovascular Disease" . "\u2026" . "Mendelian randomization; genetics; epidemiology; drug development; cardiovascular diseases"@en . . "Van Iperen, Erik PA" . "van 't Hooft, Ferdinand" . "Holmes, Michael V" . "Carruthers, Kathryn F" . "11"^^ . "Baldassarre, Damiano" . "Leusink, Maarten" . "Brunisholz, Kimberly D" . "Franco-Cereceda, Anders" . . "0735-1097" . "Goel, Anuj" . . "RIV/00023001:_____/13:00058759!RIV14-MZ0-00023001" . . "Beutner, Frank" . . "Swerdlow, Daniel I" . "Simon, Tabassome" . . "Brenner, Hermann" . "10.1016/j.jacc.2013.06.044" . "113"^^ . "Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. Background Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Conclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events. (C) 2013 by the American College of Cardiology Foundation"@en . "Dehghan, Abbas" . "Gertow, Karl" . . "Kuchenbaecker, Karoline B" . . . "Secretory Phospholipase A(2)-IIA and Cardiovascular Disease"@en . . "N" . "Journal of the American College of Cardiology" . "3"^^ . "Nelson, Christopher P" . "Navis, Gerjan J" . "Cooper, Jackie A" . "Leach, Irene Mateo" . "Asselbergs, Folkert W" . "Haase, Christiane L" . "Hovingh, G. Kees" . "de Faire, Ulf" . "Tedgui, Alain" . . . "Palmen, Jutta" . "Mega, Jessica L" . "Secretory Phospholipase A(2)-IIA and Cardiovascular Disease" . "Thiery, Joachim" . . "Hofker, Marten H" . "Danchin, Nicolas" . "Tremoli, Elena" . "Verschuren, Jeffrey JW" . . "Panayiotou, Andrie G" . "Horne, Benjamin D" . "000326939500010" . "104378" . "Holdt, Lesca M" . "62" . "[BA2A64A52CE8]" .