Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

被引：127

作者：

Nioi, P. ^{[1
]}

Sigurdsson, A. ^{[1
]}

Thorleifsson, G. ^{[1
,6
]}

Helgason, H. ^{[1
,3
]}

Agustsdottir, A. B. ^{[1
]}

Norddahl, G. L. ^{[1
]}

Helgadottir, A. ^{[1
,2
]}

Magnusdottir, A. ^{[1
]}

Jonasdottir, A. ^{[1
]}

Gretarsdottir, S. ^{[1
]}

Jonsdottir, I. ^{[1
,2
]}

Steinthorsdottir, V. ^{[1
]}

Rafnar, T. ^{[1
]}

Swinkels, D. W. ^{[8
]}

Galesloot, T. E. ^{[9
]}

Grarup, N. ^{[11
]}

Jorgensen, T. ^{[12
,13
,14
]}

Vestergaard, H. ^{[11
]}

Hansen, T. ^{[11
,15
]}

Lauritzen, T. ^{[16
]}

Linneberg, A. ^{[12
,13
,17
]}

Friedrich, N. ^{[21
]}

Krarup, N. T. ^{[11
]}

Fenger, M. ^{[18
]}

Abildgaard, U. ^{[19
]}

Hansen, P. R. ^{[19
]}

Galloe, A. M. ^{[19
,20
]}

Braund, P. S. ^{[22
,23
]}

Nelson, C. P. ^{[22
,23
]}

Hall, A. S. ^{[24
]}

Williams, M. J. A. ^{[26
]}

van Rij, A. M. ^{[27
]}

Jones, G. T. ^{[27
]}

Patel, R. S. ^{[25
,28
]}

Levey, A. I. ^{[28
]}

Hayek, S. ^{[28
]}

Shah, S. H. ^{[29
]}

Reilly, M. ^{[30
]}

Eyjolfsson, G. I. ^{[4
]}

Sigurdardottir, O. ^{[7
]}

Olafsson, I. ^{[5
]}

Kiemeney, L. A. ^{[9
,10
]}

Quyyumi, A. A. ^{[28
]}

Rader, D. J. ^{[30
]}

Kraus, W. E. ^{[29
]}

Samani, N. J. ^{[22
,23
]}

Pedersen, O. ^{[11
]}

Thorgeirsson, G. ^{[2
]}

Masson, G. ^{[1
]}

Holm, H. ^{[1
,6
]}

机构：

[1] DeCODE Genet Amgen, Sturlugata 8, IS-101 Reykjavik, Iceland

[2] Univ Iceland, Fac Med, Reykjavik, Iceland

[3] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

[4] Natl Univ Hosp Iceland, Lab Mjodd, Landspitali, Reykjavik, Iceland

[5] Natl Univ Hosp Iceland, Dept Clin Biochem, Landspitali, Reykjavik, Iceland

[6] Natl Univ Hosp Iceland, Dept Internal Med, Div Cardiol, Landspitali, Reykjavik, Iceland

[7] Akureyri Hosp, Dept Clin Biochem, Akureyri, Iceland

[8] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Nijmegen, Netherlands

[9] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, Nijmegen, Netherlands

[10] Radboud Univ Nijmegen, Med Ctr, Dept Hlth Evidence, Nijmegen, Netherlands

[11] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark

[12] Univ Copenhagen, Fac Hlth & Med Sci, Inst Publ Hlth, Copenhagen, Denmark

[13] Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark

[14] Aalborg Univ, Fac Med, Aalborg, Denmark

[15] Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark

[16] Univ Aarhus, Dept Publ Hlth, Sect Gen Practice, Aarhus, Denmark

[17] Rigshosp, Dept Clin Expt Res, Glostrup, Denmark

[18] Univ Hosp Copenhagen Hvidovre, Dept Clin Biochem, Hvidovre, Denmark

[19] Gentofte Univ Hosp, Dept Cardiol, Hellerup, Denmark

[20] Roskilde Hosp, Dept Cardiol, Roskilde, Denmark

[21] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany

[22] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[23] Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England

[24] Univ Leeds, Leeds Inst Genet Hlth & Therapeut, Leeds, W Yorkshire, England

[25] UCL, Inst Cardiovasc Sci, London, England

[26] Univ Otago, Dept Med, Dunedin Sch Med, Dunedin, New Zealand

[27] Univ Otago, Dept Surg, Dunedin Sch Med, Dunedin, New Zealand

[28] Emory Univ, Sch Med, Atlanta, GA USA

[29] Duke Univ, Sch Med, Durham, NC USA

[30] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2016年 / 374卷 / 22期

基金：

美国国家卫生研究院;

关键词：

AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA; FAMILIAL HYPERCHOLESTEROLEMIA; SIALIC-ACID; ASIALOGLYCOPROTEIN; LOCUS; GLYCOPROTEINS; CHOLESTEROL; GALACTOSYL; MUTATIONS; PROTEINS;

D O I：

10.1056/NEJMoa1508419

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 = 1.0x10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P = 4.0x10(-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 = 1.8x10(-3)). CONCLUSIONS 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.)

引用

页码：2131 / 2141

页数：11

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