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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Massachusetts Medical Society
2016
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Online Access: | http://www.nejm.org/doi/full/10.1056/NEJMoa1508419#t=article http://hdl.handle.net/2381/38423 https://doi.org/10.1056/NEJMoa1508419 |
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ftleicester:oai:lra.le.ac.uk:2381/38423 |
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Open Polar |
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University of Leicester: Leicester Research Archive (LRA) |
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ftleicester |
language |
English |
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Adult Aged 80 and over Asialoglycoprotein Receptor Base Sequence Cholesterol Coronary Artery Disease European Continental Ancestry Group Female Genetic Predisposition to Disease Haploinsufficiency Humans Iceland Kaplan-Meier Estimate Male Middle Aged Molecular Sequence Data Myocardial Infarction Risk Sequence Analysis DNA |
spellingShingle |
Adult Aged 80 and over Asialoglycoprotein Receptor Base Sequence Cholesterol Coronary Artery Disease European Continental Ancestry Group Female Genetic Predisposition to Disease Haploinsufficiency Humans Iceland Kaplan-Meier Estimate Male Middle Aged Molecular Sequence Data Myocardial Infarction Risk Sequence Analysis DNA Nioi, P. Sigurdsson, A. Thorleifsson, G. Helgason, H. Agustsdottir, A. B. Norddahl, G. L. Helgadottir, A. Magnusdottir, A. Jonasdottir, A. Gretarsdottir, 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. van Rij, A. M. Jones, G. T. Patel, R. S. 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. Sulem, P. Thorsteinsdottir, U. Stefansson, K. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. |
topic_facet |
Adult Aged 80 and over Asialoglycoprotein Receptor Base Sequence Cholesterol Coronary Artery Disease European Continental Ancestry Group Female Genetic Predisposition to Disease Haploinsufficiency Humans Iceland Kaplan-Meier Estimate Male Middle Aged Molecular Sequence Data Myocardial Infarction 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. (Funded by the National Institutes of Health and others.). upported by a grant (UL1 RR025008) from the Clinical and Translational Science Award program of the National Institutes of Health (NIH), a grant (R01HL089650-02) from the National Heart, Lung, and Blood Institute, and a grant (P30NS055077) from the Emory Neuroscience National Institute of Neurological Disorders and Stroke (NINDS) Core Facilities to Emory University; an unrestricted donation from the Novo Nordisk Foundation to the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen; and grants (to Drs. Nelson and Samani) from the British Heart Foundation. Peer-reviewed Publisher Version |
format |
Article in Journal/Newspaper |
author |
Nioi, P. Sigurdsson, A. Thorleifsson, G. Helgason, H. Agustsdottir, A. B. Norddahl, G. L. Helgadottir, A. Magnusdottir, A. Jonasdottir, A. Gretarsdottir, 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. van Rij, A. M. Jones, G. T. Patel, R. S. 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. Sulem, P. Thorsteinsdottir, U. Stefansson, K. |
author_facet |
Nioi, P. Sigurdsson, A. Thorleifsson, G. Helgason, H. Agustsdottir, A. B. Norddahl, G. L. Helgadottir, A. Magnusdottir, A. Jonasdottir, A. Gretarsdottir, 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. van Rij, A. M. Jones, G. T. Patel, R. S. 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. Sulem, P. Thorsteinsdottir, U. 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. |
publisher |
Massachusetts Medical Society |
publishDate |
2016 |
url |
http://www.nejm.org/doi/full/10.1056/NEJMoa1508419#t=article http://hdl.handle.net/2381/38423 https://doi.org/10.1056/NEJMoa1508419 |
long_lat |
ENVELOPE(-45.900,-45.900,-60.633,-60.633) |
geographic |
Meier |
geographic_facet |
Meier |
genre |
Iceland |
genre_facet |
Iceland |
op_relation |
http://www.ncbi.nlm.nih.gov/pubmed/27192541 New England Journal of Medicine , 2016, 374 (22), pp. 2131-2141 0028-4793 http://www.nejm.org/doi/full/10.1056/NEJMoa1508419#t=article http://hdl.handle.net/2381/38423 doi:10.1056/NEJMoa1508419 1533-4406 |
op_rights |
Creative Commons “Attribution Non-Commercial No Derivatives” licence CC BY-NC-ND, further details of which can be found via the following link: http://creativecommons.org/licenses/by-nc-nd/4.0/ Archived with reference to SHERPA/RoMEO and publisher website. |
op_rightsnorm |
CC-BY-NC-ND |
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 |
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1766043666440257536 |
spelling |
ftleicester:oai:lra.le.ac.uk:2381/38423 2023-05-15T16:53:09+02:00 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, A. Magnusdottir, A. Jonasdottir, A. Gretarsdottir, 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. van Rij, A. M. Jones, G. T. Patel, R. S. 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. Sulem, P. Thorsteinsdottir, U. Stefansson, K. 2016-11-09T15:11:26Z http://www.nejm.org/doi/full/10.1056/NEJMoa1508419#t=article http://hdl.handle.net/2381/38423 https://doi.org/10.1056/NEJMoa1508419 en eng Massachusetts Medical Society http://www.ncbi.nlm.nih.gov/pubmed/27192541 New England Journal of Medicine , 2016, 374 (22), pp. 2131-2141 0028-4793 http://www.nejm.org/doi/full/10.1056/NEJMoa1508419#t=article http://hdl.handle.net/2381/38423 doi:10.1056/NEJMoa1508419 1533-4406 Creative Commons “Attribution Non-Commercial No Derivatives” licence CC BY-NC-ND, further details of which can be found via the following link: http://creativecommons.org/licenses/by-nc-nd/4.0/ Archived with reference to SHERPA/RoMEO and publisher website. CC-BY-NC-ND Adult Aged 80 and over Asialoglycoprotein Receptor Base Sequence Cholesterol Coronary Artery Disease European Continental Ancestry Group Female Genetic Predisposition to Disease Haploinsufficiency Humans Iceland Kaplan-Meier Estimate Male Middle Aged Molecular Sequence Data Myocardial Infarction Risk Sequence Analysis DNA Journal Article Journal Article;Research Support, N.I.H., Extramural;Research Support, Non-U.S. Gov't 2016 ftleicester https://doi.org/10.1056/NEJMoa1508419 2019-03-22T20:22:07Z 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. (Funded by the National Institutes of Health and others.). upported by a grant (UL1 RR025008) from the Clinical and Translational Science Award program of the National Institutes of Health (NIH), a grant (R01HL089650-02) from the National Heart, Lung, and Blood Institute, and a grant (P30NS055077) from the Emory Neuroscience National Institute of Neurological Disorders and Stroke (NINDS) Core Facilities to Emory University; an unrestricted donation from the Novo Nordisk Foundation to the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen; and grants (to Drs. Nelson and Samani) from the British Heart Foundation. Peer-reviewed Publisher Version Article in Journal/Newspaper Iceland University of Leicester: Leicester Research Archive (LRA) Meier ENVELOPE(-45.900,-45.900,-60.633,-60.633) New England Journal of Medicine 374 22 2131 2141 |