دورية أكاديمية
Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.
| العنوان: | Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease. |
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| المؤلفون: | 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. |
| بيانات النشر: | Massachusetts Medical Society |
| سنة النشر: | 2016 |
| المجموعة: | University of Leicester: Leicester Research Archive (LRA) |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0028-4793 1533-4406 |
| العلاقة: | http://www.ncbi.nlm.nih.gov/pubmed/27192541Test; New England Journal of Medicine , 2016, 374 (22), pp. 2131-2141; http://hdl.handle.net/2381/38423Test |
| DOI: | 10.1056/NEJMoa1508419#t=article |
| DOI: | 10.1056/NEJMoa1508419 |
| الإتاحة: | https://doi.org/10.1056/NEJMoa1508419Test http://hdl.handle.net/2381/38423Test |
| حقوق: | 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/4.0Test/ Archived with reference to SHERPA/RoMEO and publisher website. |
| رقم الانضمام: | edsbas.C819CC77 |
| قاعدة البيانات: | BASE |
| تدمد: | 00284793 15334406 |
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| DOI: | 10.1056/NEJMoa1508419#t=article |