TY - JOUR
T1 - Secretory phospholipase A2-IIA and cardiovascular disease
T2 - A mendelian randomization study
AU - Holmes-paper
AU - Holmes, Michael V.
AU - Simon, Tabassome
AU - Exeter, Holly J.
AU - Folkersen, Lasse
AU - Asselbergs, Folkert W.
AU - Guardiola, Montse
AU - Cooper, Jackie A.
AU - Palmen, Jutta
AU - Hubacek, Jaroslav A.
AU - Carruthers, Kathryn F.
AU - Horne, Benjamin D.
AU - Brunisholz, Kimberly D.
AU - Mega, Jessica L.
AU - Van Iperen, Erik P.A.
AU - Li, Mingyao
AU - Leusink, Maarten
AU - Trompet, Stella
AU - Verschuren, Jeffrey J.W.
AU - Hovingh, G. Kees
AU - Dehghan, Abbas
AU - Nelson, Christopher P.
AU - Kotti, Salma
AU - Danchin, Nicolas
AU - Scholz, Markus
AU - Haase, Christiane L.
AU - Rothenbacher, Dietrich
AU - Swerdlow, Daniel I.
AU - Kuchenbaecker, Karoline B.
AU - Staines-Urias, Eleonora
AU - Goel, Anuj
AU - Van 'T Hooft, Ferdinand
AU - Gertow, Karl
AU - De Faire, Ulf
AU - Panayiotou, Andrie G.
AU - Tremoli, Elena
AU - Baldassarre, Damiano
AU - Veglia, Fabrizio
AU - Holdt, Lesca M.
AU - Beutner, Frank
AU - Kumari, Meena
AU - Tobin, Martin D.
AU - Day, Ian N.M.
AU - Gaunt, Tom R.
AU - Sattar, Naveed
AU - Schwartz, Gregory G.
AU - Lawlor, Debbie A.
AU - Morris, Richard W.
AU - Kivimaki, Mika
AU - Anderson, Jeffrey L.
AU - Palmer, Tom M.
PY - 2013/11/19
Y1 - 2013/11/19
N2 - 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 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 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 sPLA 2 enzyme activity and MVE. Conclusions Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
AB - 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 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 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 sPLA 2 enzyme activity and MVE. Conclusions Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
KW - cardiovascular diseases
KW - drug development
KW - epidemiology
KW - genetics
KW - Mendelian randomization
UR - http://www.scopus.com/inward/record.url?scp=84888256840&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2013.06.044
DO - 10.1016/j.jacc.2013.06.044
M3 - Article (Academic Journal)
C2 - 23916927
AN - SCOPUS:84888256840
VL - 62
SP - 1966
EP - 1976
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 21
ER -