Variant ASGR1 associated with a reduced risk of coronary artery disease
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 approxima...
Published in: | New England Journal of Medicine |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
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2016
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Online Access: | https://portal.findresearcher.sdu.dk/da/publications/b6706161-0af8-4612-94e3-a4aaaa499723 https://doi.org/10.1056/NEJMoa1508419 https://findresearcher.sdu.dk/ws/files/128445298/Variant_ASGR1_associated_with_a_reduced_risk_of_coronary_artery_disease.pdf |
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ftsydanskunivpub:oai:sdu.dk:publications/b6706161-0af8-4612-94e3-a4aaaa499723 |
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Open Polar |
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University of Southern Denmark Research Portal |
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ftsydanskunivpub |
language |
English |
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Adult Aged 80 and over Asialoglycoprotein Receptor/genetics Base Sequence Cholesterol/blood Coronary Artery Disease/genetics European Continental Ancestry Group/genetics Female Genetic Predisposition to Disease Haploinsufficiency Humans Iceland Kaplan-Meier Estimate Male Middle Aged Molecular Sequence Data Myocardial Infarction/genetics Risk Sequence Analysis DNA |
spellingShingle |
Adult Aged 80 and over Asialoglycoprotein Receptor/genetics Base Sequence Cholesterol/blood Coronary Artery Disease/genetics European Continental Ancestry Group/genetics Female Genetic Predisposition to Disease Haploinsufficiency Humans Iceland Kaplan-Meier Estimate Male Middle Aged Molecular Sequence Data Myocardial Infarction/genetics Risk Sequence Analysis DNA Nioi, P. Sigurdsson, A. Thorleifsson, G. Helgason, H. Agustsdottir, A. B. Norddahl, G. L. Helgadottir, Anna Magnusdottir, A. Jonasdottir, A. Grétarsdóttir, Sólveig Jonsdottir, I Steinthorsdottir, V. Rafnar, Thorunn Swinkels, D. W. Galesloot, T. E. Grarup, N. Jørgensen, T Vestergaard, H. Hansen, Torben Lauritzen, T Linneberg, A. Friedrich, Nele Krarup, N T Fenger, Mogens Abildgaard, U. Hansen, Peter R Galløe, Anders M. Braund, P. S. Nelson, Christopher P Hall, Alistair S Williams, Michael J A van Rij, Andre M Jones, Gregory T Patel, Sanjay R Levey, Allan I Hayek, S. Shah, Svati H Reilly, Marie Eyjolfsson, G. I. Sigurdardottir, O. Olafsson, Isleifur Kiemeney, L. A. Quyyumi, Arshed A Rader, Daniel J Kraus, W. E. Samani, Nilesh J Pedersen, O. Thorgeirsson, G. Masson, G. Holm, Hilma Gudbjartsson, D. F. Sulem, P. Thorsteinsdottir, Unnur Stefansson, K Variant ASGR1 associated with a reduced risk of coronary artery disease |
topic_facet |
Adult Aged 80 and over Asialoglycoprotein Receptor/genetics Base Sequence Cholesterol/blood Coronary Artery Disease/genetics European Continental Ancestry Group/genetics Female Genetic Predisposition to Disease Haploinsufficiency Humans Iceland Kaplan-Meier Estimate Male Middle Aged Molecular Sequence Data Myocardial Infarction/genetics Risk Sequence Analysis DNA |
description |
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 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). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. Copyright © 2016 Massachusetts Medical Society. |
format |
Article in Journal/Newspaper |
author |
Nioi, P. Sigurdsson, A. Thorleifsson, G. Helgason, H. Agustsdottir, A. B. Norddahl, G. L. Helgadottir, Anna Magnusdottir, A. Jonasdottir, A. Grétarsdóttir, Sólveig Jonsdottir, I Steinthorsdottir, V. Rafnar, Thorunn Swinkels, D. W. Galesloot, T. E. Grarup, N. Jørgensen, T Vestergaard, H. Hansen, Torben Lauritzen, T Linneberg, A. Friedrich, Nele Krarup, N T Fenger, Mogens Abildgaard, U. Hansen, Peter R Galløe, Anders M. Braund, P. S. Nelson, Christopher P Hall, Alistair S Williams, Michael J A van Rij, Andre M Jones, Gregory T Patel, Sanjay R Levey, Allan I Hayek, S. Shah, Svati H Reilly, Marie Eyjolfsson, G. I. Sigurdardottir, O. Olafsson, Isleifur Kiemeney, L. A. Quyyumi, Arshed A Rader, Daniel J Kraus, W. E. Samani, Nilesh J Pedersen, O. Thorgeirsson, G. Masson, G. Holm, Hilma Gudbjartsson, D. F. Sulem, P. Thorsteinsdottir, Unnur Stefansson, K |
author_facet |
Nioi, P. Sigurdsson, A. Thorleifsson, G. Helgason, H. Agustsdottir, A. B. Norddahl, G. L. Helgadottir, Anna Magnusdottir, A. Jonasdottir, A. Grétarsdóttir, Sólveig Jonsdottir, I Steinthorsdottir, V. Rafnar, Thorunn Swinkels, D. W. Galesloot, T. E. Grarup, N. Jørgensen, T Vestergaard, H. Hansen, Torben Lauritzen, T Linneberg, A. Friedrich, Nele Krarup, N T Fenger, Mogens Abildgaard, U. Hansen, Peter R Galløe, Anders M. Braund, P. S. Nelson, Christopher P Hall, Alistair S Williams, Michael J A van Rij, Andre M Jones, Gregory T Patel, Sanjay R Levey, Allan I Hayek, S. Shah, Svati H Reilly, Marie Eyjolfsson, G. I. Sigurdardottir, O. Olafsson, Isleifur Kiemeney, L. A. Quyyumi, Arshed A Rader, Daniel J Kraus, W. E. Samani, Nilesh J Pedersen, O. Thorgeirsson, G. Masson, G. Holm, Hilma Gudbjartsson, D. F. Sulem, P. Thorsteinsdottir, Unnur Stefansson, K |
author_sort |
Nioi, P. |
title |
Variant ASGR1 associated with a reduced risk of coronary artery disease |
title_short |
Variant ASGR1 associated with a reduced risk of coronary artery disease |
title_full |
Variant ASGR1 associated with a reduced risk of coronary artery disease |
title_fullStr |
Variant ASGR1 associated with a reduced risk of coronary artery disease |
title_full_unstemmed |
Variant ASGR1 associated with a reduced risk of coronary artery disease |
title_sort |
variant asgr1 associated with a reduced risk of coronary artery disease |
publishDate |
2016 |
url |
https://portal.findresearcher.sdu.dk/da/publications/b6706161-0af8-4612-94e3-a4aaaa499723 https://doi.org/10.1056/NEJMoa1508419 https://findresearcher.sdu.dk/ws/files/128445298/Variant_ASGR1_associated_with_a_reduced_risk_of_coronary_artery_disease.pdf |
genre |
Iceland |
genre_facet |
Iceland |
op_source |
Nioi , P , Sigurdsson , A , Thorleifsson , G , Helgason , H , Agustsdottir , A B , Norddahl , G L , Helgadottir , A , Magnusdottir , A , Jonasdottir , A , Grétarsdóttir , S , Jonsdottir , I , Steinthorsdottir , V , Rafnar , T , Swinkels , D W , Galesloot , T E , Grarup , N , Jørgensen , T , Vestergaard , H , Hansen , T , Lauritzen , T , Linneberg , A , Friedrich , N , Krarup , N T , Fenger , M , Abildgaard , U , Hansen , P R , Galløe , A M , Braund , P S , Nelson , C P , Hall , A S , Williams , M J A , van Rij , A M , Jones , G T , Patel , S R , Levey , A I , Hayek , S , Shah , S H , Reilly , M , Eyjolfsson , G I , Sigurdardottir , O , Olafsson , I , Kiemeney , L A , Quyyumi , A A , Rader , D J , Kraus , W E , Samani , N J , Pedersen , O , Thorgeirsson , G , Masson , G , Holm , H , Gudbjartsson , D F , Sulem , P , Thorsteinsdottir , U & Stefansson , K 2016 , ' Variant ASGR1 associated with a reduced risk of coronary artery disease ' , The New England Journal of Medicine , vol. 374 , no. 22 , pp. 2131-2141 . https://doi.org/10.1056/NEJMoa1508419 |
op_relation |
https://portal.findresearcher.sdu.dk/da/publications/b6706161-0af8-4612-94e3-a4aaaa499723 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/10.1056/NEJMoa1508419 |
container_title |
New England Journal of Medicine |
container_volume |
374 |
container_issue |
22 |
container_start_page |
2131 |
op_container_end_page |
2141 |
_version_ |
1810452501496856576 |
spelling |
ftsydanskunivpub:oai:sdu.dk:publications/b6706161-0af8-4612-94e3-a4aaaa499723 2024-09-15T18:14:44+00:00 Variant ASGR1 associated with a reduced risk of coronary artery disease Nioi, P. Sigurdsson, A. Thorleifsson, G. Helgason, H. Agustsdottir, A. B. Norddahl, G. L. Helgadottir, Anna Magnusdottir, A. Jonasdottir, A. Grétarsdóttir, Sólveig Jonsdottir, I Steinthorsdottir, V. Rafnar, Thorunn Swinkels, D. W. Galesloot, T. E. Grarup, N. Jørgensen, T Vestergaard, H. Hansen, Torben Lauritzen, T Linneberg, A. Friedrich, Nele Krarup, N T Fenger, Mogens Abildgaard, U. Hansen, Peter R Galløe, Anders M. Braund, P. S. Nelson, Christopher P Hall, Alistair S Williams, Michael J A van Rij, Andre M Jones, Gregory T Patel, Sanjay R Levey, Allan I Hayek, S. Shah, Svati H Reilly, Marie Eyjolfsson, G. I. Sigurdardottir, O. Olafsson, Isleifur Kiemeney, L. A. Quyyumi, Arshed A Rader, Daniel J Kraus, W. E. Samani, Nilesh J Pedersen, O. Thorgeirsson, G. Masson, G. Holm, Hilma Gudbjartsson, D. F. Sulem, P. Thorsteinsdottir, Unnur Stefansson, K 2016-06-02 application/pdf https://portal.findresearcher.sdu.dk/da/publications/b6706161-0af8-4612-94e3-a4aaaa499723 https://doi.org/10.1056/NEJMoa1508419 https://findresearcher.sdu.dk/ws/files/128445298/Variant_ASGR1_associated_with_a_reduced_risk_of_coronary_artery_disease.pdf eng eng https://portal.findresearcher.sdu.dk/da/publications/b6706161-0af8-4612-94e3-a4aaaa499723 info:eu-repo/semantics/openAccess Nioi , P , Sigurdsson , A , Thorleifsson , G , Helgason , H , Agustsdottir , A B , Norddahl , G L , Helgadottir , A , Magnusdottir , A , Jonasdottir , A , Grétarsdóttir , S , Jonsdottir , I , Steinthorsdottir , V , Rafnar , T , Swinkels , D W , Galesloot , T E , Grarup , N , Jørgensen , T , Vestergaard , H , Hansen , T , Lauritzen , T , Linneberg , A , Friedrich , N , Krarup , N T , Fenger , M , Abildgaard , U , Hansen , P R , Galløe , A M , Braund , P S , Nelson , C P , Hall , A S , Williams , M J A , van Rij , A M , Jones , G T , Patel , S R , Levey , A I , Hayek , S , Shah , S H , Reilly , M , Eyjolfsson , G I , Sigurdardottir , O , Olafsson , I , Kiemeney , L A , Quyyumi , A A , Rader , D J , Kraus , W E , Samani , N J , Pedersen , O , Thorgeirsson , G , Masson , G , Holm , H , Gudbjartsson , D F , Sulem , P , Thorsteinsdottir , U & Stefansson , K 2016 , ' Variant ASGR1 associated with a reduced risk of coronary artery disease ' , The New England Journal of Medicine , vol. 374 , no. 22 , pp. 2131-2141 . https://doi.org/10.1056/NEJMoa1508419 Adult Aged 80 and over Asialoglycoprotein Receptor/genetics Base Sequence Cholesterol/blood Coronary Artery Disease/genetics European Continental Ancestry Group/genetics Female Genetic Predisposition to Disease Haploinsufficiency Humans Iceland Kaplan-Meier Estimate Male Middle Aged Molecular Sequence Data Myocardial Infarction/genetics Risk Sequence Analysis DNA article 2016 ftsydanskunivpub https://doi.org/10.1056/NEJMoa1508419 2024-08-12T23:48:15Z 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 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). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. Copyright © 2016 Massachusetts Medical Society. Article in Journal/Newspaper Iceland University of Southern Denmark Research Portal New England Journal of Medicine 374 22 2131 2141 |