Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

作者：Paul Nioi, Ásgeir Sigurðsson, Guðmar Þorleifsson, Hannes Helgason, Arna B. Agustsdottir, Gudmundur Logi Norddahl, Anna Helgadóttir, Audur Magnusdottir, Áslaug Jónasdóttir, Sólveig Grétarsdóttir, Ingileif Jónsdóttir, Valgerður Steinthórsdóttir, Þórunn Rafnar, Dorine W. Swinkels, Tessel E. Galesloot, Niels Grarup, Torben Jørgensen, Henrik Vestergaard, Torben F. Hansen, Torsten Lauritzen, Allan R Linneberg, Nele Friedrich, Nikolaj Thure Krarup, Mogens Fenger, Ulrik Abildgaard, Peter Riis Hansen, Anders Michael Galloe, Peter S. Braund, Christopher P. Nelson, Alistair S. Hall, Michael J.A. Williams, André M. van Rij, Gregory T. Jones, Riyaz S. Patel, Allan I. Levey, Salim S. Hayek, Svati Hasmukh Shah, Muredach P. Reilly, Gudmundur Ingi Eyjolfsson, Ólöf Sigurðardóttir, Ísleifur Ólafsson, Lambertus A.L.M. Kiemeney, Arshed Ali Quyyumi, Daniel James Rader, William E. Kraus, Nilesh J. Samani, Oluf Borbye Pedersen, Guðmundur Þorgeirsson, Gísli Másson, Hilma Hólm, Daniel Fannar Gudbjartsson, Patrick Sulem, Unnur Arna Thorsteinsdottir, Kāri Stefánsson · 发表于：New England Journal of Medicine · 年份：2016 · DOI：10.1056/nejmoa1508419 · 被引用次数：200 · 研究领域：Genetic Associations and Epidemiology、Glycosylation and Glycoproteins Research、Diabetes, Cardiovascular Risks, and Lipoproteins

BACKGROUND: 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. METHODS: 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. RESULTS: 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 ris...