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. (Funded by the National Institutes of Health and others.).

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. (Funded by the National Institutes of Health and others.).

U2 - 10.1056/NEJMoa1508419

DO - 10.1056/NEJMoa1508419

M3 - Journal article

C2 - 27192541

VL - 374

SP - 2131

EP - 2141

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 22

ER -