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Secretory Phospholipase A(2)-IIA and Cardiovascular Disease

Holmes, MV; Simon, T; Exeter, HJ; Folkersen, L; Asselbergs, FW; Guardiola, M; Cooper, JA; Palmen, J; Hubacek, JA; Carruthers, KF; et al. Holmes, MV; Simon, T; Exeter, HJ; Folkersen, L; Asselbergs, FW; Guardiola, M; Cooper, JA; Palmen, J; Hubacek, JA; Carruthers, KF; Horne, BD; Brunisholz, KD; Mega, JL; van Iperen, EP; Li, M; Leusink, M; Trompet, S; Verschuren, JJ; Hovingh, GK; Dehghan, A; Nelson, CP; Kotti, S; Danchin, N; Scholz, M; Haase, CL; Rothenbacher, D; Swerdlow, DI; Kuchenbaecker, KB; Staines-Urias, E; Goel, A; van 't Hooft, F; Gertow, K; de Faire, U; Panayiotou, AG; Tremoli, E; Baldassarre, D; Veglia, F; Holdt, LM; Beutner, F; Gansevoort, RT; Navis, GJ; Mateo Leach, I; Breitling, LP; Brenner, H; Thiery, J; Dallmeier, D; Franco-Cereceda, A; Boer, JM; Stephens, JW; Hofker, MH; Tedgui, A; Hofman, A; Uitterlinden, AG; Adamkova, V; Pitha, J; Onland-Moret, NC; Cramer, MJ; Nathoe, HM; Spiering, W; Klungel, OH; Kumari, M; Whincup, PH; Morrow, DA; Braund, PS; Hall, AS; Olsson, AG; Doevendans, PA; Trip, MD; Tobin, MD; Hamsten, A; Watkins, H; Koenig, W; Nicolaides, AN; Teupser, D; Day, IN; Carlquist, JF; Gaunt, TR; Ford, I; Sattar, N; Tsimikas, S; Schwartz, GG; Lawlor, DA; Morris, RW; Sandhu, MS; Poledne, R; Maitland-van der Zee, AH; Khaw, KT; Keating, BJ; van der Harst, P; Price, JF; Mehta, SR; Yusuf, S; Witteman, JC; Franco, OH; Jukema, JW; de Knijff, P; Tybjaerg-Hansen, A; Rader, DJ; Farrall, M; Samani, NJ; Kivimaki, M; Fox, KA; Humphries, SE; Anderson, JL; Boekholdt, SM; Palmer, TM; Eriksson, P; Paré, G; Hingorani, AD; Sabatine, MS; Mallat, Z; Casas, JP; Talmud, PJ (2013) Secretory Phospholipase A(2)-IIA and Cardiovascular Disease. JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 62 (21). 1966 - 1976 (11). ISSN 0735-1097 https://doi.org/10.1016/j.jacc.2013.06.044
SGUL Authors: Whincup, Peter Hynes

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Abstract

Objectives This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. Background Higher circulating levels of sPLA2-IIA mass or sPLA2 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 sPLA2 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 sPLA2-IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 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 sPLA2-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 sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

Item Type: Article
Additional Information: PubMed ID: 23916927
Keywords: ACS, CI, LDL-C, MI, MVE, Mendelian randomization, OR, RCT, SNP, acute coronary syndrome(s), cardiovascular diseases, confidence interval, drug development, epidemiology, genetics, low-density lipoprotein cholesterol, major vascular events, myocardial infarction, odds ratio, randomized clinical trial, sPLA(2), secretory phospholipase A(2), single-nucleotide polymorphism, Alleles, Cardiovascular Diseases, DNA, Gene Expression Regulation, Humans, Incidence, Mendelian Randomization Analysis, Phospholipases A2, Secretory, World Health, Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Cardiovascular System & Cardiology, CARDIAC & CARDIOVASCULAR SYSTEMS, cardiovascular diseases, drug development, epidemiology, genetics, Mendelian randomization, ACUTE CORONARY SYNDROMES, MENDELIAN RANDOMIZATION, ARTERY-DISEASE, EPIC-NORFOLK, SERUM-LEVELS, HEALTHY-MEN, EVENTS, TRIAL, INHIBITOR, RISK
SGUL Research Institute / Research Centre: Academic Structure > Population Health Research Institute (INPH)
Journal or Publication Title: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
ISSN: 0735-1097
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Dates:
DateEvent
19 November 2013Published
PubMed ID: 23916927
Web of Science ID: 23916927
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URI: https://openaccess.sgul.ac.uk/id/eprint/103331
Publisher's version: https://doi.org/10.1016/j.jacc.2013.06.044

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