From deCODE Genetics-Amgen (P.N., A.S., G. Thorleifsson, H. Helgason, A.B.A., G.L.N., A.H., A.M., A.J., S.G., I.J., V.S., T.R., G.M., H. Holm, D.G., P.S., U.T., K.S.), Faculty of Medicine (A.H., I.J., G. Thorgeirsson, U.T., K.S.) and School of Engineering and Natural Sciences (H. Helgason, D.G.), University of Iceland, the Laboratory in Mjodd (G.I.E.), and the Department of Clinical Biochemistry (I.O.) and Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, H. Holm), Landspitali, National University Hospital of Iceland, Reykjavik, and the Department of Clinical Biochemistry, Akureyri Hospital, Akureyri (O.S.) - all in Iceland; Radboud Institute for Molecular Life Sciences, Department of Laboratory Medicine (D.W.S.), Radboud Institute for Health Sciences (T.E.G., L.A.K.), and the Department of Health Evidence (L.A.K.), Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands; Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics (N.G., H.V., T.H., N.T.K., O.P.), and Institute of Public Health, Faculty of Health and Medical Science (T.J., A.L.), University of Copenhagen, and Research Center for Prevention and Health, Capital Region of Denmark (T.J., A.L.), Copenhagen, Faculty of Medicine, University of Aalborg, Aalborg (T.J.), Faculty of Health Sciences, University of Southern Denmark, Odense (T.H.), Department of Public Health, Section of General Practice, University of Aarhus, Aarhus (T.L.), Department of Clinical Experimental Research, Rigshospitalet, Glostrup (A.L.), Department of Clinical Biochemistry, University Hospital of Copenhagen at Hvidovre, Hvidovre (M.F.), Department of Cardiology, Gentofte University Hospital, Hellerup (U.A., P.R.H., A.M.G.), and Department of Cardiology, Roskilde Hospital, Roskilde (A.M.G.) - all in Denmark; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany (N.F.); Department of Cardiovascular Sciences, Uni
N Engl J Med. 2016 Jun 2;374(22):2131-41. doi: 10.1056/NEJMoa1508419. Epub 2016 May 18.
Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.
We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.
We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)).
ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).
已知几种序列变异会影响非高密度脂蛋白（HDL）胆固醇的血清水平，从而改变冠心病的风险。
我们对 2636 名冰岛人的基因组进行测序，并发现了一些变体，然后将这些变体导入大约 398000 名冰岛人的基因组中。我们在 119146 个样本中检测了这些导入变体与非高密度脂蛋白胆固醇水平之间的关联。然后，我们在两个欧洲血统的人群中进行了复制测试。我们评估了一个涉及功能丧失的变体在 42524 名病例患者和 249414 名对照者的 5 个欧洲血统人群中的冠心病风险中的作用。在一个靶基因中筛选了一组额外的基因组，以寻找其他功能丧失的变体。我们评估了一个涉及变体对蛋白质稳定性的影响。
我们在 ASGR1 的内含子 4 中发现了一个罕见的 12 碱基对（bp）缺失（del12），该基因编码一种糖蛋白受体的亚基，糖蛋白受体是一种在循环糖蛋白的动态平衡中起作用的凝集素。del12 突变激活了一个隐蔽的剪接位点，导致移码突变和一个过早的终止密码子，使截短的蛋白质易于降解。该突变的杂合子携带者（在我们的研究人群中每 120 人中有 1 人）的非高密度脂蛋白胆固醇水平低于非携带者，差异为 15.3 毫克/分升（0.40mmol/L）（P=1.0×10(-16)），冠心病的风险也较低（降低 34%；95%置信区间，21 至 45%；P=4.0×10(-6)）。在冰岛人更大的测序样本中，我们发现了另一种功能丧失的 ASGR1 变体（p.W158X，每 1850 人中有 1 人携带），也与非高密度脂蛋白胆固醇水平较低有关（P=1.8×10(-3)）。
ASGR1 杂合不足与非高密度脂蛋白胆固醇水平降低和冠心病风险降低有关。（由美国国立卫生研究院等资助）。
