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Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.

Publication ,  Journal Article
Nioi, P; Sigurdsson, A; Thorleifsson, G; Helgason, H; Agustsdottir, AB; Norddahl, GL; Helgadottir, A; Magnusdottir, A; Jonasdottir, A; Rafnar, T ...
Published in: N Engl J Med
June 2, 2016

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.).

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Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

June 2, 2016

Volume

374

Issue

22

Start / End Page

2131 / 2141

Location

United States

Related Subject Headings

  • White People
  • Sequence Analysis, DNA
  • Risk
  • Myocardial Infarction
  • Molecular Sequence Data
  • Middle Aged
  • Male
  • Kaplan-Meier Estimate
  • Iceland
  • Humans
 

Citation

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Nioi, P., Sigurdsson, A., Thorleifsson, G., Helgason, H., Agustsdottir, A. B., Norddahl, G. L., … Stefansson, K. (2016). Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. N Engl J Med, 374(22), 2131–2141. https://doi.org/10.1056/NEJMoa1508419
Nioi, Paul, Asgeir Sigurdsson, Gudmar Thorleifsson, Hannes Helgason, Arna B. Agustsdottir, Gudmundur L. Norddahl, Anna Helgadottir, et al. “Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.N Engl J Med 374, no. 22 (June 2, 2016): 2131–41. https://doi.org/10.1056/NEJMoa1508419.
Nioi P, Sigurdsson A, Thorleifsson G, Helgason H, Agustsdottir AB, Norddahl GL, et al. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. N Engl J Med. 2016 Jun 2;374(22):2131–41.
Nioi, Paul, et al. “Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.N Engl J Med, vol. 374, no. 22, June 2016, pp. 2131–41. Pubmed, doi: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. Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. N Engl J Med. 2016 Jun 2;374(22):2131–2141.

Published In

N Engl J Med

DOI

EISSN

1533-4406

Publication Date

June 2, 2016

Volume

374

Issue

22

Start / End Page

2131 / 2141

Location

United States

Related Subject Headings

  • White People
  • Sequence Analysis, DNA
  • Risk
  • Myocardial Infarction
  • Molecular Sequence Data
  • Middle Aged
  • Male
  • Kaplan-Meier Estimate
  • Iceland
  • Humans