Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

Paul Nioi; Asgeir Sigurdsson; Gudmar Thorleifsson; Hannes Helgason; Arna B Agustsdottir; Gudmundur L Norddahl; Anna Helgadottir; Audur Magnusdottir; Aslaug Jonasdottir; Solveig Gretarsdottir; Ingileif Jonsdottir; Valgerdur Steinthorsdottir; Thorunn Rafnar; Dorine W Swinkels; Tessel E Galesloot; Niels Grarup; Torben Jørgensen; Henrik Vestergaard; Torben Hansen; Torsten Lauritzen; Allan Linneberg; Nele Friedrich; Nikolaj T Krarup; Mogens Fenger; Ulrik Abildgaard; Peter R Hansen; Anders M Galløe; Peter S Braund; Christopher P Nelson; Alistair S Hall; Michael J A Williams; Andre M van Rij; Gregory T Jones; Riyaz S Patel; Allan I Levey; Salim Hayek; Svati H Shah; Muredach Reilly; Gudmundur I Eyjolfsson; Olof Sigurdardottir; Isleifur Olafsson; Lambertus A Kiemeney; Arshed A Quyyumi; Daniel J Rader; William E Kraus; Nilesh J Samani; Oluf Pedersen; Gudmundur Thorgeirsson; Gisli Masson; Hilma Holm; Daniel Gudbjartsson; Patrick Sulem; Unnur Thorsteinsdottir; Kari Stefansson

doi:10.1056/nejmoa1508419

Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

Paul Nioi, Asgeir Sigurdsson, Gudmar Thorleifsson, Hannes Helgason, Arna B Agustsdottir, Gudmundur L Norddahl, Anna Helgadottir, Audur Magnusdottir, Aslaug Jonasdottir, Solveig Gretarsdottir, Ingileif Jonsdottir, Valgerdur Steinthorsdottir, Thorunn Rafnar, Dorine W Swinkels, Tessel E Galesloot, Niels Grarup, Torben Jørgensen, Henrik Vestergaard, Torben Hansen, Torsten LauritzenAllan Linneberg, Nele Friedrich, Nikolaj T Krarup, Mogens Fenger, Ulrik Abildgaard, Peter R Hansen, Anders M Galløe, Peter S Braund, Christopher P Nelson, Alistair S Hall, Michael J A Williams, Andre M van Rij, Gregory T Jones, Riyaz S Patel, Allan I Levey, Salim Hayek, Svati H Shah, Muredach Reilly, Gudmundur I Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Lambertus A Kiemeney, Arshed A Quyyumi, Daniel J Rader, William E Kraus, Nilesh J Samani, Oluf Pedersen, Gudmundur Thorgeirsson, Gisli Masson, Hilma Holm, Daniel Gudbjartsson, Patrick Sulem, Unnur Thorsteinsdottir, Kari Stefansson

66 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	New England Journal of Medicine
Vol/bind	374
Udgave nummer	22
Sider (fra-til)	2131-2141
Antal sider	11
ISSN	0028-4793
DOI	https://doi.org/10.1056/nejmoa1508419
Status	Udgivet - 2 jun. 2016

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10.1056/nejmoa1508419

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1508419

Citationsformater

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., ... Stefansson, K. (2016). Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. New England Journal of Medicine, 374(22), 2131-2141. https://doi.org/10.1056/nejmoa1508419

Nioi, P, Sigurdsson, A, Thorleifsson, G, Helgason, H, Agustsdottir, AB, Norddahl, GL, Helgadottir, A, Magnusdottir, A, Jonasdottir, A, Gretarsdottir, S, Jonsdottir, I, Steinthorsdottir, V, Rafnar, T, Swinkels, DW, Galesloot, TE, Grarup, N, Jørgensen, T, Vestergaard, H , Hansen, T, Lauritzen, T, Linneberg, A, Friedrich, N, Krarup, NT, Fenger, M, Abildgaard, U, Hansen, PR, Galløe, AM, Braund, PS, Nelson, CP, Hall, AS, Williams, MJA, van Rij, AM, Jones, GT, Patel, RS, Levey, AI, Hayek, S, Shah, SH, Reilly, M, Eyjolfsson, GI, Sigurdardottir, O, Olafsson, I, Kiemeney, LA, Quyyumi, AA, Rader, DJ, Kraus, WE, Samani, NJ, Pedersen, O, Thorgeirsson, G, Masson, G, Holm, H, Gudbjartsson, D, Sulem, P, Thorsteinsdottir, U & Stefansson, K 2016, 'Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease', New England Journal of Medicine, bind 374, nr. 22, s. 2131-2141. https://doi.org/10.1056/nejmoa1508419

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title = "Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease",

abstract = "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.",

author = "Paul Nioi and Asgeir Sigurdsson and Gudmar Thorleifsson and Hannes Helgason and Agustsdottir, {Arna B} and Norddahl, {Gudmundur L} and Anna Helgadottir and Audur Magnusdottir and Aslaug Jonasdottir and Solveig Gretarsdottir and Ingileif Jonsdottir and Valgerdur Steinthorsdottir and Thorunn Rafnar and Swinkels, {Dorine W} and Galesloot, {Tessel E} and Niels Grarup and Torben J{\o}rgensen and Henrik Vestergaard and Torben Hansen and Torsten Lauritzen and Allan Linneberg and Nele Friedrich and Krarup, {Nikolaj T} and Mogens Fenger and Ulrik Abildgaard and Hansen, {Peter R} and Gall{\o}e, {Anders M} and Braund, {Peter S} and Nelson, {Christopher P} and Hall, {Alistair S} and Williams, {Michael J A} and {van Rij}, {Andre M} and Jones, {Gregory T} and Patel, {Riyaz S} and Levey, {Allan I} and Salim Hayek and Shah, {Svati H} and Muredach Reilly and Eyjolfsson, {Gudmundur I} and Olof Sigurdardottir and Isleifur Olafsson and Kiemeney, {Lambertus A} and Quyyumi, {Arshed A} and Rader, {Daniel J} and Kraus, {William E} and Samani, {Nilesh J} and Oluf Pedersen and Gudmundur Thorgeirsson and Gisli Masson and Hilma Holm and Daniel Gudbjartsson and Patrick Sulem and Unnur Thorsteinsdottir and Kari Stefansson",

year = "2016",

month = jun,

day = "2",

doi = "10.1056/nejmoa1508419",

language = "English",

volume = "374",

pages = "2131--2141",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "22",

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TY - JOUR

T1 - Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

AU - Nioi, Paul

AU - Sigurdsson, Asgeir

AU - Thorleifsson, Gudmar

AU - Helgason, Hannes

AU - Agustsdottir, Arna B

AU - Norddahl, Gudmundur L

AU - Helgadottir, Anna

AU - Magnusdottir, Audur

AU - Jonasdottir, Aslaug

AU - Gretarsdottir, Solveig

AU - Jonsdottir, Ingileif

AU - Steinthorsdottir, Valgerdur

AU - Rafnar, Thorunn

AU - Swinkels, Dorine W

AU - Galesloot, Tessel E

AU - Grarup, Niels

AU - Jørgensen, Torben

AU - Vestergaard, Henrik

AU - Hansen, Torben

AU - Lauritzen, Torsten

AU - Linneberg, Allan

AU - Friedrich, Nele

AU - Krarup, Nikolaj T

AU - Fenger, Mogens

AU - Abildgaard, Ulrik

AU - Hansen, Peter R

AU - Galløe, Anders M

AU - Braund, Peter S

AU - Nelson, Christopher P

AU - Hall, Alistair S

AU - Williams, Michael J A

AU - van Rij, Andre M

AU - Jones, Gregory T

AU - Patel, Riyaz S

AU - Levey, Allan I

AU - Hayek, Salim

AU - Shah, Svati H

AU - Reilly, Muredach

AU - Eyjolfsson, Gudmundur I

AU - Sigurdardottir, Olof

AU - Olafsson, Isleifur

AU - Kiemeney, Lambertus A

AU - Quyyumi, Arshed A

AU - Rader, Daniel J

AU - Kraus, William E

AU - Samani, Nilesh J

AU - Pedersen, Oluf

AU - Thorgeirsson, Gudmundur

AU - Masson, Gisli

AU - Holm, Hilma

AU - Gudbjartsson, Daniel

AU - Sulem, Patrick

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

PY - 2016/6/2

Y1 - 2016/6/2

N2 - 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.

AB - 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.

U2 - 10.1056/nejmoa1508419

DO - 10.1056/nejmoa1508419

M3 - Journal article

C2 - 27192541

SN - 0028-4793

VL - 374

SP - 2131

EP - 2141

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 22

ER -

Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease

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