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Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease
Paul Nioi1, Asgeir Sigurdsson1, Gudmar Thorleifsson1
1From deCODE Genetics-Amgen (P.N., A.S., G. Thorleifsson, H. Helgason, A.B.A., G.L.N., A.H., A.M., A.J., S.G., I.J., V.S., T.R., G.M., H. Holm, D.G., P.S., U.T., K.S.), Faculty of Medicine (A.H., I.J., G. Thorgeirsson, U.T., K.S.) and School of Engineering and Natural Sciences (H. Helgason, D.G.), University of Iceland, the Laboratory in Mjodd (G.I.E.), and the Department of Clinical Biochemistry (I.O.) and Division of Cardiology, Department of Internal Medicine (G. Thorgeirsson, H. Holm), Landspitali, National University Hospital of Iceland, Reykjavik, and the Department of Clinical Biochemistry, Akureyri Hospital, Akureyri (O.S.) - all in Iceland; Radboud Institute for Molecular Life Sciences, Department of Laboratory Medicine (D.W.S.), Radboud Institute for Health Sciences (T.E.G., L.A.K.), and the Department of Health Evidence (L.A.K.), Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands; Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics (N.G., H.V., T.H., N.T.K., O.P.), and Institute of Public Health, Faculty of Health and Medical Science (T.J., A.L.), University of Copenhagen, and Research Center for Prevention and Health, Capital Region of Denmark (T.J., A.L.), Copenhagen, Faculty of Medicine, University of Aalborg, Aalborg (T.J.), Faculty of Health Sciences, University of Southern Denmark, Odense (T.H.), Department of Public Health, Section of General Practice, University of Aarhus, Aarhus (T.L.), Department of Clinical Experimental Research, Rigshospitalet, Glostrup (A.L.), Department of Clinical Biochemistry, University Hospital of Copenhagen at Hvidovre, Hvidovre (M.F.), Department of Cardiology, Gentofte University Hospital, Hellerup (U.A., P.R.H., A.M.G.), and Department of Cardiology, Roskilde Hospital, Roskilde (A.M.G.) - all in Denmark; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany (N.F.); Department of Cardiovascular Sciences, Uni
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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