血管生成素样蛋白4的失活变异与冠状动脉疾病风险
Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease.
作者信息
Dewey Frederick E, Gusarova Viktoria, O'Dushlaine Colm, Gottesman Omri, Trejos Jesus, Hunt Charleen, Van Hout Cristopher V, Habegger Lukas, Buckler David, Lai Ka-Man V, Leader Joseph B, Murray Michael F, Ritchie Marylyn D, Kirchner H Lester, Ledbetter David H, Penn John, Lopez Alexander, Borecki Ingrid B, Overton John D, Reid Jeffrey G, Carey David J, Murphy Andrew J, Yancopoulos George D, Baras Aris, Gromada Jesper, Shuldiner Alan R
机构信息
From the Regeneron Genetics Center (F.E.D., C.O., O.G., C.V.V.H., L.H., J.P., A.L., I.B.B., J.D.O., J.G.R., A.J.M., G.D.Y., A.B., J.G., A.R.S.) and Regeneron Pharmaceuticals (V.G., J.T., C.H., D.B., K.-M.V.L., A.J.M., G.D.Y.) - both in Tarrytown, NY; and Geisinger Health System, Danville, PA (J.B.L., M.F.M., M.D.R., H.L.K., D.H.L., D.J.C.).
出版信息
N Engl J Med. 2016 Mar 24;374(12):1123-33. doi: 10.1056/NEJMoa1510926. Epub 2016 Mar 2.
BACKGROUND
Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides.
METHODS
We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys.
RESULTS
We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels.
CONCLUSIONS
Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.).
背景
循环甘油三酯水平高于正常是缺血性心血管疾病的一个危险因素。脂蛋白脂肪酶的激活可降低循环甘油三酯水平，而血管生成素样4（ANGPTL4）可抑制该酶的活性。
方法
在DiscovEHR人类遗传学研究中，我们对42930名主要为欧洲血统参与者的样本中的ANGPTL4外显子进行了测序。我们对脂质水平与错义E40K变异（与血浆甘油三酯水平降低有关）及其他失活突变之间进行了关联测试。然后，我们在10552名冠心病患者和29223名对照中测试了冠心病与E40K变异及其他失活突变之间的关联。我们还测试了一种抗ANGPTL4人单克隆抗体对小鼠和猴子脂质水平的影响。
结果
我们鉴定出1661名E40K变异杂合子、17名纯合子，以及75名在ANGPTL4中有13种其他单等位基因失活突变的参与者。E40K变异携带者的甘油三酯水平比非携带者低13%，高密度脂蛋白（HDL）胆固醇水平比非携带者高7%。E40K变异携带者患冠心病的可能性也显著低于非携带者（比值比，0.81；95%置信区间，0.70至0.92；P=0.002）。K40纯合子的甘油三酯水平明显低于杂合子，HDL胆固醇水平高于杂合子。其他失活突变的携带者也有较低的甘油三酯水平和较高的HDL胆固醇水平，且患冠心病的可能性低于非携带者。在小鼠和猴子中，单克隆抗体抑制Angptl4可降低甘油三酯水平。
结论
ANGPTL4中E40K及其他失活突变的携带者甘油三酯水平较低，患冠心病的风险也低于非携带者。在小鼠和猴子中抑制Angptl4也导致这些指标相应降低。（由再生元制药公司资助。）
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