Talmud Philippa J, Smart Melissa, Presswood Edward, Cooper Jackie A, Nicaud Viviane, Drenos Fotios, Palmen Jutta, Marmot Michael G, Boekholdt S Matthijs, Wareham Nicholas J, Khaw Kay-Tee, Kumari Meena, Humphries Steve E
Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, 5 University St, London WC1E 6JF, United Kingdom.
Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2319-25. doi: 10.1161/ATVBAHA.108.176917. Epub 2008 Oct 30.
Angiopoietin-like 4 is a dual-function protein: an inhibitor of LPL, influencing plasma triglycerides (TGs), with angiogenic properties. We examined the association of common ANGPTL4 variants with CHD traits and risk in 5 studies (13,527 individuals).
The effects on plasma lipids of 6 tagging SNPs and the recently identified E40K were examined in a study of 2772 men. Only T266M (rs1044250, MAF=30%) and E40K (MAF=2%) were significantly associated with TG-lowering (-10.4%, P<0.004 and -20.4%, P<0.0001), respectively. T266M no longer showed significant associations when K40 carriers (K40+) were excluded (P=0.2). Combining data from 5 studies confirmed the TG-lowering effect of K40+ (weighted mean difference: -0.12 [95% CI -0.18, -0.05] mmol/L TG P=0.0001). Surprisingly, in the 3 prospective studies, the combined OR for CHD was 1.48 (1.11 to 1.96, P=0.007), independent of TG. In individuals with a paternal history of MI (n=332) T266M, but not E40K, showed effects on postprandial AUC TG and glucose (P=0.009 and P=0.017, respectively) compared to controls (n=370).
Although associated with an atheroprotective lipid profile, E40K was associated with increased CHD risk, suggesting Angptl4 influences parameters beyond lipid levels. T266M showed effects only under conditions of postprandial stress. The functionality of these potential "loss-of-function" variants needs validation.
血管生成素样蛋白4是一种具有双重功能的蛋白质：它是脂蛋白脂肪酶的抑制剂，可影响血浆甘油三酯（TGs），并具有血管生成特性。我们在5项研究（共13527名个体）中研究了常见的血管生成素样蛋白4（ANGPTL4）变体与冠心病特征及风险之间的关联。
在一项对2772名男性的研究中，检测了6个标签单核苷酸多态性（SNP）以及最近发现的E40K对血脂的影响。只有T266M（rs1044250，小等位基因频率[MAF]=30%）和E40K（MAF=2%）分别与甘油三酯降低显著相关（-10.4%，P<0.004和-20.4%，P<0.0001）。当排除携带K40的个体（K40+）后，T266M不再显示出显著关联（P=0.2）。合并5项研究的数据证实了K40+具有降低甘油三酯的作用（加权平均差：-0.12[95%置信区间-0.18，-0.05]mmol/L甘油三酯，P=0.0001）。令人惊讶的是，在3项前瞻性研究中，冠心病的合并比值比为1.48（1.11至1.96，P=0.007），与甘油三酯无关。在有心肌梗死家族史的个体（n=332）中，与对照组（n=370）相比，T266M而非E40K对餐后甘油三酯曲线下面积（AUC TG）和葡萄糖有影响（分别为P=0.009和P=0.017）。
尽管E40K与具有抗动脉粥样硬化作用的血脂谱相关，但它与冠心病风险增加有关，这表明血管生成素样蛋白4影响的参数超出了血脂水平。T266M仅在餐后应激条件下有影响。这些潜在的“功能丧失”变体的功能需要进一步验证。
