Secretory Phospholipase A(2)-IIA and Cardiovascular Disease

MV Holmes; T Simon; HJ Exeter; L Folkersen; FW Asselbergs; M Guardiola; JA Cooper; J Palmen; JA Hubacek; KF Carruthers; BD Horne; KD Brunisholz; JL Mega; EPA Van Iperen; MY Li; M Leusink; S Trompet; JJW Verschuren; GK Hovingh; Abbas Dehghan; CP Nelson; S Kotti; N Danchin; Markus Scholz; CL Haase; D Rothenbacher; DI Swerdlow; KB Kuchenbaecker; E Staines-Urias; A Goel; F van 't Hooft; K Gertow; U de Faire; AG Panayiotou; E Tremoli; D Baldassarre; F Veglia; LM Holdt; F Beutner; RT Gansevoort; GJ Navis; IM Leach; LP Breitling; H Brenner; J Thiery; D Dallmeier; A Franco-Cereceda; JMA Boer; JW Stephens; MH Hofker; A Tedgui; Bert Hofman; André Uitterlinden; V Adamkova; J Pitha; NC Onland-Moret; MJ Cramer; HM Nathoe; W Spiering; OH Klungel; M Kumari; PH Whincup; DA Morrow; PS Braund; AS Hall; AG Olsson; PA Doevendans; MD Trip; MD Tobin; A Hamsten; H Watkins; W Koenig; AN Nicolaides; D Teupser; INM Day; JF Carlquist; TR Gaunt; I Ford; N Sattar; S Tsimikas; GG Schwartz; DA Lawlor; RW Morris; MS Sandhu; R Poledne; AH Zee; KT Khaw; BJ Keating; P van der Harst; JF Price; SR Mehta; S Yusuf; JCM Witteman; OH Franco Duran; JW Jukema; P de Knijff; A Tybjaerg-Hansen; DJ Rader; M Farrall; NJ Samani; M Kivimaki; KAA Fox; SE Humphries; JL Anderson; SM Boekholdt; TM Palmer; P Eriksson; G Pare; AD Hingorani; MS Sabatine; Z Mallat; JP Casas; PJ Talmud

doi:10.1016/j.jacc.2013.06.044

Secretory Phospholipase A(2)-IIA and Cardiovascular Disease

MV Holmes, T Simon, HJ Exeter, L Folkersen, FW Asselbergs, M Guardiola, JA Cooper, J Palmen, JA Hubacek, KF Carruthers, BD Horne, KD Brunisholz, JL Mega, EPA Van Iperen, MY Li, M Leusink, S Trompet, JJW Verschuren, GK Hovingh, Abbas DehghanCP Nelson, S Kotti, N Danchin, Markus Scholz, CL Haase, D Rothenbacher, DI Swerdlow, KB Kuchenbaecker, E Staines-Urias, A Goel, F van 't Hooft, K Gertow, U de Faire, AG Panayiotou, E Tremoli, D Baldassarre, F Veglia, LM Holdt, F Beutner, RT Gansevoort, GJ Navis, IM Leach, LP Breitling, H Brenner, J Thiery, D Dallmeier, A Franco-Cereceda, JMA Boer, JW Stephens, MH Hofker, A Tedgui, Bert Hofman, André Uitterlinden, V Adamkova, J Pitha, NC Onland-Moret, MJ Cramer, HM Nathoe, W Spiering, OH Klungel, M Kumari, PH Whincup, DA Morrow, PS Braund, AS Hall, AG Olsson, PA Doevendans, MD Trip, MD Tobin, A Hamsten, H Watkins, W Koenig, AN Nicolaides, D Teupser, INM Day, JF Carlquist, TR Gaunt, I Ford, N Sattar, S Tsimikas, GG Schwartz, DA Lawlor, RW Morris, MS Sandhu, R Poledne, AH Zee, KT Khaw, BJ Keating, P van der Harst, JF Price, SR Mehta, S Yusuf, JCM Witteman, OH Franco Duran, JW Jukema, P de Knijff, A Tybjaerg-Hansen, DJ Rader, M Farrall, NJ Samani, M Kivimaki, KAA Fox, SE Humphries, JL Anderson, SM Boekholdt, TM Palmer, P Eriksson, G Pare, AD Hingorani, MS Sabatine, Z Mallat, JP Casas, PJ Talmud

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Abstract

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 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

Original language	English
Pages (from-to)	1966-1976
Number of pages	11
Journal	Journal of the American College of Cardiology
Volume	62
Issue number	21
DOIs	https://doi.org/10.1016/j.jacc.2013.06.044
Publication status	Published - 2013

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jacc.2013.06.044

http://hdl.handle.net/1765/72323

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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, EPA., Li, MY., Leusink, M., Trompet, S., Verschuren, JJW., Hovingh, GK., ... Talmud, PJ. (2013). Secretory Phospholipase A(2)-IIA and Cardiovascular Disease. Journal of the American College of Cardiology, 62(21), 1966-1976. https://doi.org/10.1016/j.jacc.2013.06.044

@article{69370045c1084135b6e68051e8a30102,

title = "Secretory Phospholipase A(2)-IIA and Cardiovascular Disease",

abstract = "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 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",

author = "MV Holmes and T Simon and HJ Exeter and L Folkersen and FW Asselbergs and M Guardiola and JA Cooper and J Palmen and JA Hubacek and KF Carruthers and BD Horne and KD Brunisholz and JL Mega and {Van Iperen}, EPA and MY Li and M Leusink and S Trompet and JJW Verschuren and GK Hovingh and Abbas Dehghan and CP Nelson and S Kotti and N Danchin and Markus Scholz and CL Haase and D Rothenbacher and DI Swerdlow and KB Kuchenbaecker and E Staines-Urias and A Goel and {van 't Hooft}, F and K Gertow and {de Faire}, U and AG Panayiotou and E Tremoli and D Baldassarre and F Veglia and LM Holdt and F Beutner and RT Gansevoort and GJ Navis and IM Leach and LP Breitling and H Brenner and J Thiery and D Dallmeier and A Franco-Cereceda and JMA Boer and JW Stephens and MH Hofker and A Tedgui and Bert Hofman and Andr{\'e} Uitterlinden and V Adamkova and J Pitha and NC Onland-Moret and MJ Cramer and HM Nathoe and W Spiering and OH Klungel and M Kumari and PH Whincup and DA Morrow and PS Braund and AS Hall and AG Olsson and PA Doevendans and MD Trip and MD Tobin and A Hamsten and H Watkins and W Koenig and AN Nicolaides and D Teupser and INM Day and JF Carlquist and TR Gaunt and I Ford and N Sattar and S Tsimikas and GG Schwartz and DA Lawlor and RW Morris and MS Sandhu and R Poledne and AH Zee and KT Khaw and BJ Keating and {van der Harst}, P and JF Price and SR Mehta and S Yusuf and JCM Witteman and {Franco Duran}, OH and JW Jukema and {de Knijff}, P and A Tybjaerg-Hansen and DJ Rader and M Farrall and NJ Samani and M Kivimaki and KAA Fox and SE Humphries and JL Anderson and SM Boekholdt and TM Palmer and P Eriksson and G Pare and AD Hingorani and MS Sabatine and Z Mallat and JP Casas and PJ Talmud",

year = "2013",

doi = "10.1016/j.jacc.2013.06.044",

language = "English",

volume = "62",

pages = "1966--1976",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier Inc.",

number = "21",

}

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, EPA, Li, MY, Leusink, M, Trompet, S, Verschuren, JJW, 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, Leach, IM, Breitling, LP, Brenner, H, Thiery, J, Dallmeier, D, Franco-Cereceda, A, Boer, JMA, Stephens, JW, Hofker, MH, Tedgui, A, Hofman, B , Uitterlinden, A, 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, INM, Carlquist, JF, Gaunt, TR, Ford, I, Sattar, N, Tsimikas, S, Schwartz, GG, Lawlor, DA, Morris, RW, Sandhu, MS, Poledne, R, Zee, AH, Khaw, KT, Keating, BJ, van der Harst, P, Price, JF, Mehta, SR, Yusuf, S, Witteman, JCM, Franco Duran, OH, Jukema, JW, de Knijff, P, Tybjaerg-Hansen, A, Rader, DJ, Farrall, M, Samani, NJ, Kivimaki, M, Fox, KAA, Humphries, SE, Anderson, JL, Boekholdt, SM, Palmer, TM, Eriksson, P, Pare, 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, vol. 62, no. 21, pp. 1966-1976. https://doi.org/10.1016/j.jacc.2013.06.044

TY - JOUR

T1 - Secretory Phospholipase A(2)-IIA and Cardiovascular Disease

AU - Holmes, MV

AU - Simon, T

AU - Exeter, HJ

AU - Folkersen, L

AU - Asselbergs, FW

AU - Guardiola, M

AU - Cooper, JA

AU - Palmen, J

AU - Hubacek, JA

AU - Carruthers, KF

AU - Horne, BD

AU - Brunisholz, KD

AU - Mega, JL

AU - Van Iperen, EPA

AU - Li, MY

AU - Leusink, M

AU - Trompet, S

AU - Verschuren, JJW

AU - Hovingh, GK

AU - Dehghan, Abbas

AU - Nelson, CP

AU - Kotti, S

AU - Danchin, N

AU - Scholz, Markus

AU - Haase, CL

AU - Rothenbacher, D

AU - Swerdlow, DI

AU - Kuchenbaecker, KB

AU - Staines-Urias, E

AU - Goel, A

AU - van 't Hooft, F

AU - Gertow, K

AU - de Faire, U

AU - Panayiotou, AG

AU - Tremoli, E

AU - Baldassarre, D

AU - Veglia, F

AU - Holdt, LM

AU - Beutner, F

AU - Gansevoort, RT

AU - Navis, GJ

AU - Leach, IM

AU - Breitling, LP

AU - Brenner, H

AU - Thiery, J

AU - Dallmeier, D

AU - Franco-Cereceda, A

AU - Boer, JMA

AU - Stephens, JW

AU - Hofker, MH

AU - Tedgui, A

AU - Hofman, Bert

AU - Uitterlinden, André

AU - Adamkova, V

AU - Pitha, J

AU - Onland-Moret, NC

AU - Cramer, MJ

AU - Nathoe, HM

AU - Spiering, W

AU - Klungel, OH

AU - Kumari, M

AU - Whincup, PH

AU - Morrow, DA

AU - Braund, PS

AU - Hall, AS

AU - Olsson, AG

AU - Doevendans, PA

AU - Trip, MD

AU - Tobin, MD

AU - Hamsten, A

AU - Watkins, H

AU - Koenig, W

AU - Nicolaides, AN

AU - Teupser, D

AU - Day, INM

AU - Carlquist, JF

AU - Gaunt, TR

AU - Ford, I

AU - Sattar, N

AU - Tsimikas, S

AU - Schwartz, GG

AU - Lawlor, DA

AU - Morris, RW

AU - Sandhu, MS

AU - Poledne, R

AU - Zee, AH

AU - Khaw, KT

AU - Keating, BJ

AU - van der Harst, P

AU - Price, JF

AU - Mehta, SR

AU - Yusuf, S

AU - Witteman, JCM

AU - Franco Duran, OH

AU - Jukema, JW

AU - de Knijff, P

AU - Tybjaerg-Hansen, A

AU - Rader, DJ

AU - Farrall, M

AU - Samani, NJ

AU - Kivimaki, M

AU - Fox, KAA

AU - Humphries, SE

AU - Anderson, JL

AU - Boekholdt, SM

AU - Palmer, TM

AU - Eriksson, P

AU - Pare, G

AU - Hingorani, AD

AU - Sabatine, MS

AU - Mallat, Z

AU - Casas, JP

AU - Talmud, PJ

PY - 2013

Y1 - 2013

N2 - 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 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

AB - 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 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

U2 - 10.1016/j.jacc.2013.06.044

DO - 10.1016/j.jacc.2013.06.044

M3 - Article

SN - 0735-1097

VL - 62

SP - 1966

EP - 1976

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 21

ER -

Secretory Phospholipase A(2)-IIA and Cardiovascular Disease

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