Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR-Reference-Cited by-同舟云学术

Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR

Published:2021-02 Issue:1 Volume:14 Page:
ISSN:2574-8300
Container-title:Circulation: Genomic and Precision Medicine
language:en
Short-container-title:Circ: Genomic and Precision Medicine

Author:

Bjornsson Eythor¹²³^ORCID,Gunnarsdottir Kristbjorg¹^ORCID,Halldorsson Gisli H.¹,Sigurdsson Asgeir¹,Arnadottir Gudny A.¹,Jonsson Hakon¹,Olafsdottir Eva F.³,Niehus Sebastian⁴⁵^ORCID,Kehr Birte⁴⁵^ORCID,Sveinbjörnsson Gardar¹,Gudmundsdottir Steinunn¹^ORCID,Helgadottir Anna¹^ORCID,Andersen Karl²³^ORCID,Thorleifsson Gudmar¹³^ORCID,Eyjolfsson Gudmundur I.⁶,Olafsson Isleifur⁷,Sigurdardottir Olof⁸^ORCID,Saemundsdottir Jona¹,Jonsdottir Ingileif¹²,Magnusson Olafur Th.¹,Masson Gisli¹^ORCID,Stefansson Hreinn¹,Gudbjartsson Daniel F.¹⁹,Thorgeirsson Gudmundur¹³^ORCID,Holm Hilma¹^ORCID,Halldorsson Bjarni V.¹¹⁰^ORCID,Melsted Pall¹⁹,Norddahl Gudmundur L.¹^ORCID,Sulem Patrick¹^ORCID,Thorsteinsdottir Unnur¹²^ORCID,Stefansson Kari¹²

Affiliation:

1. deCODE genetics/Amgen, Inc (E.B., K.G., G.H.H., A.S., G.A.A., H.J., G.S., S.G., A.H., G. Thorleifsson, J.S., I.J., O.T.M., G.M., H.S., D.F.G., G. Thorgeirsson, H.H., B.V.H., P.M., G.L.N., P.S., U.T., K.S.), University of Iceland.

2. Faculty of Medicine (E.B., K.A., I.J., U.T., K.S.), University of Iceland.

3. Department of Internal Medicine (E.B., E.F.O.), Division of Cardiology, Department of Internal Medicine (K.A., G. Thorgeirsson), Landspítali - The National University Hospital of Iceland, Reykjavík.

4. Berlin Institute of Health (S.N., B.K.), Humboldt-Universität zu Berlin & Berlin Institute of Health, Berlin, Germany.

5. Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin (S.N., B.K.), Humboldt-Universität zu Berlin & Berlin Institute of Health, Berlin, Germany.

6. The Laboratory in Mjódd, Reykjavík (G.I.E.).

7. Department of Clinical Biochemistry (I.O.), Landspítali - The National University Hospital of Iceland, Reykjavík.

8. Department of Clinical Biochemistry, Akureyri Hospital (O.S.).

9. School of Engineering and Natural Sciences (D.F.G., P.M.), University of Iceland.

10. School of Science and Engineering, Reykjavík University, Iceland (B.V.H.).

Abstract

Background: Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene ( LDLR ) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels. Methods: We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes. Results: We discovered a 2.5-kb deletion (del2.5) overlapping the 3′ untranslated region of LDLR in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL; P =8.4×10 − 8 ). Del2.5 results in production of an alternative mRNA isoform with a truncated 3′ untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of LDLR . In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform ( P =0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers ( P =0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers. Conclusions: Del2.5 is the first reported gain-of-function mutation in LDLR causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of LDLR mRNA as a potent regulator of LDL receptor expression in humans.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

General Medicine

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