Novel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA2)-V isoenzyme in coronary heart disease: modified Mendelian randomization analysis using PLA2G5 expression levels.

Holmes, Michael V; Exeter, Holly J; Folkersen, Lasse; Nelson, Christopher P; Guardiola, Montse; Cooper, Jackie A; Sofat, Reecha; Boekholdt, S Matthijs; Khaw, Kay-Tee; Li, Ka-Wah; Smith, Andrew J P; Van't Hooft, Ferdinand; Eriksson, Per; Franco-Cereceda, Anders; Asselbergs, Folkert W; Boer, Jolanda M A; Onland-Moret, N Charlotte; Hofker, Marten; Erdmann, Jeanette; Kivimaki, Mika; Kumari, Meena; Reiner, Alex P; Keating, Brendan J; Humphries, Steve E; Hingorani, Aroon D; Mallat, Ziad; Samani, Nilesh J; Talmud, Philippa J; CARDIoGRAM Consortium; Kathiresan, Sekar; Reilly, Muredach P; Samani, Nilesh J; Schunkert, Heribert; Erdmann, Jeanette; Boerwinkle, Eric; Erdmann, Jeanette; Hall, Alistair; Hengstenberg, Christian; Kathiresan, Sekar; König, Inke R; Laaksonen, Reijo; McPherson, Ruth; Reilly, Muredach P; Samani, Nilesh J; Schunkert, Heribert; Thompson, John R; Thorsteinsdottir, Unnur; Ziegler, Andreas; König, Inke R; Thompson, John R; Absher, Devin; Chen, Li; Cupples, L Adrienne; Halperin, Eran; Li, Mingyao; Musunuru, Kiran; Preuss, Michael; Schillert, Arne; Thorleifsson, Gudmar; Voight, Benjamin F; Wells, George A; Assimes, Themistocles L; Deloukas, Panos; Erdmann, Jeanette; Holm, Hilma; Kathiresan, Sekar; König, Inke R; McPherson, Ruth; Reilly, Muredach P; Roberts, Robert; Samani, Nilesh J; Schunkert, Heribert; Stewart, Alexandre F R; Absher, Devin; Assimes, Themistocles L; Fortmann, Stephen; Go, Alan; Hlatky, Mark; Iribarren, Carlos; Knowles, Joshua; Myers, Richard; Quertermous, Thomas; Sidney, Steven; Risch, Neil; Tang, Hua; Blankenberg, Stefan; Zeller, Tanja; Schillert, Arne; Wild, Philipp; Ziegler, Andreas; Schnabel, Renate; Sinning, Christoph; Lackner, Karl; Tiret, Laurence; Nicaud, Viviane; Cambien, Francois; Bickel, Christoph; Rupprecht, Hans J; Perret, Claire; Proust, Carole; Münzel, Thomas; Barbalic, Maja; Bis, Joshua; Boerwinkle, Eric; Chen, Ida Yii-Der; Cupples, L Adrienne; Dehghan, Abbas; Demissie-Banjaw, Serkalem; Folsom, Aaron; Glazer, Nicole; Gudnason, Vilmundur; Harris, Tamara; Heckbert, Susan; Levy, Daniel; Lumley, Thomas; Marciante, Kristin; Morrison, Alanna; Donnell, Christopher J; Psaty, Bruce M; Rice, Kenneth; Rotter, Jerome I; Siscovick, David S; Smith, Nicholas; Smith, Albert; Taylor, Kent D; van Duijn, Cornelia; Volcik, Kelly; Whitteman, Jaqueline; Ramachandran, Vasan; Hofman, Albert; Uitterlinden, Andre; Gretarsdottir, Solveig; Gulcher, Jeffrey R; Holm, Hilma; Kong, Augustine; Stefansson, Kari; Thorgeirsson, Gudmundur; Andersen, Karl; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Erdmann, Jeanette; Fischer, Marcus; Grosshennig, Anika; Hengstenberg, Christian; König, Inke R; Lieb, Wolfgang; Linsel-Nitschke, Patrick; Preuss, Michael; Stark, Klaus; Schreiber, Stefan; Wichmann, H -Erich; Ziegler, Andreas; Schunkert, Heribert; Aherrahrou, Zouhair; Bruse, Petra; Doering, Angela; Erdmann, Jeanette; Hengstenberg, Christian; Illig, Thomas; Klopp, Norman; König, Inke R; Linsel-Nitschke, Patrick; Loley, Christina; Medack, Anja; Meisinger, Christina; Meitinger, Thomas; Nahrstedt, Janja; Peters, Annette; Preuss, Michael; Stark, Klaus; Wagner, Arnika K; Wichmann, H -Erich; Willenborg, Christina; Ziegler, Andreas; Schunkert, Heribert; Böhm, Bernhard O; Dobnig, Harald; Grammer, Tanja B; Halperin, Eran; Hoffmann, Michael M; Kleber, Marcus; Laaksonen, Reijo; März, Winfried; Meinitzer, Andreas; Winkelmann, Bernhard R; Pilz, Stefan; Renner, Wilfried; Scharnagl, Hubert; Stojakovic, Tatjana; Tomaschitz, Andreas; Winkler, Karl; Voight, Benjamin F; Musunuru, Kiran; Guiducci, Candace; Burtt, Noel; Gabriel, Stacey B; Siscovick, David S; Elosua, Roberto; Peltonen, Leena; Salomaa, Veikko; Schwartz, Stephen M; Melander, Olle; Altshuler, David; Kathiresan, Sekar; Stewart, Alexandre F R; Chen, Li; Dandona, Sonny; Wells, George A; Jarinova, Olga; McPherson, Ruth; Roberts, Robert; Reilly, Muredach P; Li, Mingyao; Qu, Liming; Wilensky, Robert; Matthai, William; Hakonarson, Hakon H; Devaney, Joe; Burnett, Mary Susan; Pichard, Augusto D; Kent, Kenneth M; Satler, Lowell; Lindsay, Joseph M; Waksman, Ron; Knouff, Christopher W; Waterworth, Dawn M; Walker, Max C; Mooser, Vincent; Epstein, Stephen E; Rader, Daniel J; Samani, Nilesh J; Thompson, John R; Braund, Peter S; Nelson, Christopher P; Wright, Benjamin J; Balmforth, Anthony J; Ball, Stephen G; Hall, Alastair S     «

Holmes, Michael V; Exeter, Holly J; Folkersen, Lasse; Nelson, Christopher P; Guardiola, Montse; Cooper, Jackie A; Sofat, Reecha; Boekholdt, S Matthijs; Khaw, Kay-Tee; Li, Ka-Wah; Smith, Andrew J P; Van't Hooft, Ferdinand; Eriksson, Per; Franco-Cereceda, Anders; Asselbergs, Folkert W; Boer, Jolanda M A; Onland-Moret, N Charlotte; Hofker, Marten; Erdmann, Jeanette; Kivimaki, Mika; Kumari, Meena; Reiner, Alex P; Keating, Brendan J; Humphries, Steve E; Hingorani, Aroon D; Mallat, Ziad; Samani, Niles...     »

Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis.Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in 4 prospective and 14 case-control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression (P=5.1×10(-6)). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95% confidence intervals [-0.9%, 1.6%]; P=0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P=0.20).This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.     «

Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRN...     »