دورية أكاديمية
Missense variants in SORT1 are associated with LDL-C in an Amish population.
| العنوان: | Missense variants in SORT1 are associated with LDL-C in an Amish population. |
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| المؤلفون: | Mitok KA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA., Schueler KL; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA., King SM; Department of Pediatrics, University of California-San Francisco, San Francisco, CA, USA., Orr J; Department of Pediatrics, University of California-San Francisco, San Francisco, CA, USA., Ryan KA; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA., Keller MP; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA., Krauss RM; Department of Pediatrics, University of California-San Francisco, San Francisco, CA, USA., Mitchell BD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA., Shuldiner AR; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; Regeneron Genetics Center, Tarrytown, NY, USA., Attie AD; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA. Electronic address: adattie@wisc.edu. |
| المصدر: | Journal of lipid research [J Lipid Res] 2023 Dec; Vol. 64 (12), pp. 100468. Date of Electronic Publication: 2023 Oct 31. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 0376606 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1539-7262 (Electronic) Linking ISSN: 00222275 NLM ISO Abbreviation: J Lipid Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: Memphis, Lipid Research, inc. |
| مواضيع طبية MeSH: | Genome-Wide Association Study* , Amish*, Humans ; Mice ; Animals ; Cholesterol, LDL/genetics ; Mice, Inbred C57BL ; Cholesterol ; Adaptor Proteins, Vesicular Transport/genetics ; Adaptor Proteins, Vesicular Transport/metabolism |
| مستخلص: | Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly associated with low-density lipoprotein cholesterol (LDL-C) in human genome-wide association studies. However, validation studies in mice and cell lines have produced variable results regarding the directionality of the effect of SORT1 on LDL-C. This, together with the fact that the 1p13.3 variants are associated with expression of several genes, has raised the question of whether SORT1 is the causal gene at this locus. Using whole exome sequencing in members of an Amish population, we identified coding variants in SORT1 that are associated with increased (rs141749679, K302E) and decreased (rs149456022, Q225H) LDL-C. Further, analysis of plasma lipoprotein particle subclasses by ion mobility in a subset of rs141749679 (K302E) carriers revealed higher levels of large LDL particles compared to noncarriers. In contrast to the effect of these variants in the Amish, the sortilin K302E mutation introduced into a C57BL/6J mouse via CRISPR/Cas9 resulted in decreased non-high-density lipoprotein cholesterol, and the sortilin Q225H mutation did not alter cholesterol levels in mice. This is indicative of different effects of these mutations on cholesterol metabolism in the two species. To our knowledge, this is the first evidence that naturally occurring coding variants in SORT1 are associated with LDL-C, thus supporting SORT1 as the gene responsible for the association of the 1p13.3 locus with LDL-C. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| معلومات مُعتمدة: | R01 DK101573 United States DK NIDDK NIH HHS; P30 DK072488 United States DK NIDDK NIH HHS; U01 HL072515 United States HL NHLBI NIH HHS; P30 AG028747 United States AG NIA NIH HHS; R01 DK102948 United States DK NIDDK NIH HHS; R01 AG018728 United States AG NIA NIH HHS; U01 GM074518 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: LDL/metabolism; SORT1; cholesterol/metabolism; dyslipidemias; genetic association; genetic linkage; lipoproteins/metabolism; lipoproteins/receptors; missense variant; sortilin |
| المشرفين على المادة: | 0 (Cholesterol, LDL) Z020Y8WIJ4 (sortilin) 97C5T2UQ7J (Cholesterol) 0 (Adaptor Proteins, Vesicular Transport) |
| تواريخ الأحداث: | Date Created: 20231101 Date Completed: 20231225 Latest Revision: 20240130 |
| رمز التحديث: | 20240130 |
| مُعرف محوري في PubMed: | PMC10711479 |
| DOI: | 10.1016/j.jlr.2023.100468 |
| PMID: | 37913995 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1539-7262 |
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| DOI: | 10.1016/j.jlr.2023.100468 |