Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease.

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Abstrakt

Tytuł:: Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease.
Autorzy:: Selvarajan I; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Toropainen A; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Garske KM; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
López Rodríguez M; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Ko A; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Miao Z; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Kaminska D; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio campus PO Box 1627, 70211 Kuopio, Finland.
Õunap K; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Örd T; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Ravindran A; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Liu OH; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Moreau PR; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Jawahar Deen A; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Männistö V; Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Pan C; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Levonen AL; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Lusis AJ; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Heikkinen S; School of Medicine, Institutes of Biomedicine and Clinical Medicine, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland.
Romanoski CE; Department of Cellular and Molecular Medicine, The College of Medicine, The University of Arizona, Tucson, AZ 85721, USA.
Pihlajamäki J; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio campus PO Box 1627, 70211 Kuopio, Finland; Departments of Medicine, Endocrinology, and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland.
Pajukanta P; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Kaikkonen MU; A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland. Electronic address: .
Źródło:: American journal of human genetics [Am J Hum Genet] 2021 Mar 04; Vol. 108 (3), pp. 411-430. Date of Electronic Publication: 2021 Feb 23.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: 2008- : [Cambridge, MA] : Cell Press
Original Publication: Baltimore, American Society of Human Genetics.
MeSH Terms:: Genetic Predisposition to Disease*
Coronary Artery Disease/*genetics
Enhancer Elements, Genetic/*genetics
Quantitative Trait Loci/*genetics
Alleles ; Chromatin/genetics ; Coronary Artery Disease/pathology ; Female ; Genome-Wide Association Study/methods ; Genomics ; Humans ; Liver/metabolism ; Male ; Molecular Sequence Annotation ; Organ Specificity/genetics ; Polymorphism, Single Nucleotide/genetics ; Promoter Regions, Genetic/genetics ; Protein Binding/genetics ; Risk Factors
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Grant Information:: R01 HL147187 United States HL NHLBI NIH HHS; P30 ES006694 United States ES NIEHS NIH HHS; R01 DK117850 United States DK NIDDK NIH HHS; P01 HL028481 United States HL NHLBI NIH HHS; R01 HL147883 United States HL NHLBI NIH HHS; F31 HL142180 United States HL NHLBI NIH HHS; U01 DK105561 United States DK NIDDK NIH HHS; R01 HL095056 United States HL NHLBI NIH HHS
Contributed Indexing:: Keywords: CRISPR; GWAS; SNP; STARR-seq; cholesterol; coronary artery disease; enhancer; functional genomics; hepatocyte; liver
Substance Nomenclature:: 0 (Chromatin)
Entry Date(s):: Date Created: 20210224 Date Completed: 20210324 Latest Revision: 20211111
Update Code:: 20240105
PubMed Central ID:: PMC8008493
DOI:: 10.1016/j.ajhg.2021.02.006
PMID:: 33626337
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Genetic factors underlying coronary artery disease (CAD) have been widely studied using genome-wide association studies (GWASs). However, the functional understanding of the CAD loci has been limited by the fact that a majority of GWAS variants are located within non-coding regions with no functional role. High cholesterol and dysregulation of the liver metabolism such as non-alcoholic fatty liver disease confer an increased risk of CAD. Here, we studied the function of non-coding single-nucleotide polymorphisms in CAD GWAS loci located within liver-specific enhancer elements by identifying their potential target genes using liver cis-eQTL analysis and promoter Capture Hi-C in HepG2 cells. Altogether, 734 target genes were identified of which 121 exhibited correlations to liver-related traits. To identify potentially causal regulatory SNPs, the allele-specific enhancer activity was analyzed by (1) sequence-based computational predictions, (2) quantification of allele-specific transcription factor binding, and (3) STARR-seq massively parallel reporter assay. Altogether, our analysis identified 1,277 unique SNPs that display allele-specific regulatory activity. Among these, susceptibility enhancers near important cholesterol homeostasis genes (APOB, APOC1, APOE, and LIPA) were identified, suggesting that altered gene regulatory activity could represent another way by which genetic variation regulates serum lipoprotein levels. Using CRISPR-based perturbation, we demonstrate how the deletion/activation of a single enhancer leads to changes in the expression of many target genes located in a shared chromatin interaction domain. Our integrative genomics approach represents a comprehensive effort in identifying putative causal regulatory regions and target genes that could predispose to clinical manifestation of CAD by affecting liver function.
(Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

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