Division of Cardiology, Cardiovascular Genome Center, Yonsei University College of Medicine, Yonsei, South Korea.
PLoS One. 2011 Apr 5;6(4):e18208. doi: 10.1371/journal.pone.0018208.
The Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA₂) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA₂ in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted.
METHODOLOGY/PRINCIPAL FINDINGS: PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66-0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69-0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA₂ activity and CAD risk.
Natural deficiency in Lp-PLA₂ activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA₂ and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.
亚洲特异性 PLA2G7 994G-T 颠换导致脂蛋白相关磷脂酶 A2（Lp-PLA₂）中的 V279F 取代，导致血浆中酶活性缺失。这种变体提供了一个独特的自然实验，以评估 Lp-PLA₂ 在人类冠心病（CAD）发病机制中的作用。鉴于大多数小型研究的结果相互矛盾，因此需要进行一项大型的两阶段病例对照研究。
方法/主要发现：首先在 2890 名 60 岁以下确诊为 CAD 的男性病例和 3128 名 50 岁及以上无 CAD 的男性对照中比较了 PLA2G7 V279F 基因型，随后在第二个独立的男性 CAD 病例 877 例和对照 1230 例的数据集进行了比较。在第一个数据集，病例组 279F 缺失等位基因的患病率为 11.5%，对照组为 12.8%。在调整年龄、体重指数、糖尿病、吸烟、血糖和血脂水平后，该等位基因患 CAD 的 OR（95%CI）为 0.80（0.66-0.97，p=0.02）。在第二个数据集，尽管效力较低，但结果非常相似，病例组等位基因频率为 11.2%，对照组为 12.5%，导致合并 OR 为 0.80（0.69-0.92），p=0.002。这种遗传效应的大小和方向与血浆 Lp-PLA₂活性与 CAD 风险的大型流行病学研究完全一致。
由于携带 PLA2G7 279F 等位基因，Lp-PLA₂ 活性的自然缺乏可预防韩国男性 CAD。这些结果为 Lp-PLA₂ 与 CAD 之间存在因果关系提供了证据，并支持抑制该酶作为预防 CAD 的创新方法。
