Stitziel Nathan O, Khera Amit V, Wang Xiao, Bierhals Andrew J, Vourakis A Christina, Sperry Alexandra E, Natarajan Pradeep, Klarin Derek, Emdin Connor A, Zekavat Seyedeh M, Nomura Akihiro, Erdmann Jeanette, Schunkert Heribert, Samani Nilesh J, Kraus William E, Shah Svati H, Yu Bing, Boerwinkle Eric, Rader Daniel J, Gupta Namrata, Frossard Philippe M, Rasheed Asif, Danesh John, Lander Eric S, Gabriel Stacey, Saleheen Danish, Musunuru Kiran, Kathiresan Sekar
Cardiovascular Division, Department of Medicine, Department of Genetics, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
J Am Coll Cardiol. 2017 Apr 25;69(16):2054-2063. doi: 10.1016/j.jacc.2017.02.030. Epub 2017 Apr 3.
Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.
The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.
We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.
The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).
ANGPTL3 deficiency is associated with protection from CAD.
家族性联合低脂血症是一种孟德尔遗传病，其特征是三大主要脂质成分均大幅降低，由血管生成素样3（ANGPTL3）基因失活突变引起。ANGPTL3缺乏是否能降低冠状动脉疾病（CAD）风险尚不清楚。
本研究旨在利用三条不同的证据线索——一个包含完全（复合杂合子）ANGPTL3缺乏个体的家族、一项基于人群的部分（杂合子）ANGPTL3缺乏人群研究以及心肌梗死（MI）患者的生物标志物水平——来检验ANGPTL3缺乏是否与CAD低风险相关。
我们使用计算机断层扫描血管造影术评估了3名完全ANGPTL3缺乏个体和3名野生型一级亲属的冠状动脉粥样硬化负担。在人群中，在多达21980名CAD患者和158200名对照受试者中确定了ANGPTL3功能丧失（LOF）突变。LOF突变被定义为无义、移码和剪接位点变异，以及在小鼠模型中导致野生型ANGPTL3活性低于25%的错义变异。在一项生物标志物研究中，测量了1493名MI患者和3232名对照受试者的循环ANGPTL3浓度。
3名完全ANGPTL3缺乏个体未显示冠状动脉粥样硬化斑块的证据。ANGPTL3基因测序表明，约每309人中就有1人是LOF突变的杂合携带者。与未突变者相比，ANGPTL3 LOF突变的杂合携带者循环甘油三酯降低17%，低密度脂蛋白胆固醇降低12%。携带者状态与CAD发病几率降低34%相关（比值比：0.66；95%置信区间：0.44至0.98；p = 0.04）。循环ANGPTL3浓度处于最低三分位数的个体与最高三分位数个体相比，MI发病几率降低（调整后比值比：0.65；95%置信区间：0.55至0.77；p < 0.001）。
ANGPTL3缺乏与预防CAD相关。
