Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.
Abstract | BACKGROUND: 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:
|
Authors | 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 |
Journal | The New England journal of medicine
(N Engl J Med)
Vol. 374
Issue 22
Pg. 2131-41
(Jun 02 2016)
ISSN: 1533-4406 [Electronic] United States |
PMID | 27192541
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- ASGR1 protein, human
- Asialoglycoprotein Receptor
- Cholesterol
|
Topics |
- Adult
- Aged
- Aged, 80 and over
- Asialoglycoprotein Receptor
(genetics)
- Base Sequence
- Cholesterol
(blood)
- Coronary Artery Disease
(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
- White People
(genetics)
|
|
Join CureHunter, for free Research Interface BASIC access!
Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease.
Find out why thousands of doctors, pharma researchers and patient activists
around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!
|