Faculty of Population Health Sciences, University College London, London, United Kingdom.
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Department of Clinical Pharmacology, URC-EST, Paris, France; Université Pierre et Marie Curie, Paris, France; INSERM, U 698, Paris, France.
J Am Coll Cardiol. 2013 Nov 19;62(21):1966-1976. doi: 10.1016/j.jacc.2013.06.044. Epub 2013 Jul 31.
This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.
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.
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.
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.
Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
本研究旨在探讨分泌型磷脂酶 A2（sPLA2）-IIA 在心血管疾病中的作用。
较高的循环 sPLA2-IIA 质量或 sPLA2 酶活性与心血管事件风险增加相关。然而，这种关联是否具有因果关系尚不清楚。最近一项 sPLA2 抑制剂（varespladib）的 III 期临床试验因缺乏疗效而提前终止。
我们对 19 项一般人群研究（74683 人中有 8021 例新发、7513 例既往主要血管事件[MVE]）和 10 项急性冠脉综合征（ACS）队列（18355 人中有 2520 例复发性 MVE）进行了孟德尔随机化荟萃分析，使用 rs11573156（编码 sPLA2-IIA 同工酶的 PLA2G2A 中的变体）作为工具变量。
PLA2G2A rs11573156 C 等位基因与循环 sPLA2-IIA 质量降低（38%至 44%）和 sPLA2 酶活性降低（3%至 23%）相关。在一般人群中，rs11573156 C 等位基因与 MVE 的比值比（OR）为 1.02（95%置信区间[CI]：0.98 至 1.06），在 ACS 队列中为 0.96（95%CI：0.90 至 1.03）。在一般人群研究中，遗传工具变量分析得出的 MVE 与 sPLA2-IIA 质量降低 1 个对数单位的 OR 为 1.04（95%CI：0.96 至 1.13），与非遗传观察性估计值（OR：0.69；95%CI：0.61 至 0.79）不同。在 ACS 队列中，遗传工具变量和观察性 OR 均显示与 MVE 无关联。工具变量分析未能显示 sPLA2 酶活性与 MVE 之间的关联。
降低 sPLA2-IIA 质量不太可能成为预防心血管事件的有用治疗目标。
