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Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274

BACKGROUND: Common chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflamm...

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Autores principales: Meckelmann, Sven W., Hawksworth, Jade I., White, Daniel, Andrews, Robert, Rodrigues, Patricia, O’Connor, Anne, Alvarez-Jarreta, Jorge, Tyrrell, Victoria J., Hinz, Christine, Zhou, You, Williams, Julie, Aldrovandi, Maceler, Watkins, William J., Engler, Adam J., Lo Sardo, Valentina, Slatter, David A., Allen, Stuart M., Acharya, Jay, Mitchell, Jacquie, Cooper, Jackie, Aoki, Junken, Kano, Kuniyuki, Humphries, Steve E., O’Donnell, Valerie B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299226/
https://www.ncbi.nlm.nih.gov/pubmed/32396387
http://dx.doi.org/10.1161/CIRCGEN.119.002806
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author Meckelmann, Sven W.
Hawksworth, Jade I.
White, Daniel
Andrews, Robert
Rodrigues, Patricia
O’Connor, Anne
Alvarez-Jarreta, Jorge
Tyrrell, Victoria J.
Hinz, Christine
Zhou, You
Williams, Julie
Aldrovandi, Maceler
Watkins, William J.
Engler, Adam J.
Lo Sardo, Valentina
Slatter, David A.
Allen, Stuart M.
Acharya, Jay
Mitchell, Jacquie
Cooper, Jackie
Aoki, Junken
Kano, Kuniyuki
Humphries, Steve E.
O’Donnell, Valerie B.
author_facet Meckelmann, Sven W.
Hawksworth, Jade I.
White, Daniel
Andrews, Robert
Rodrigues, Patricia
O’Connor, Anne
Alvarez-Jarreta, Jorge
Tyrrell, Victoria J.
Hinz, Christine
Zhou, You
Williams, Julie
Aldrovandi, Maceler
Watkins, William J.
Engler, Adam J.
Lo Sardo, Valentina
Slatter, David A.
Allen, Stuart M.
Acharya, Jay
Mitchell, Jacquie
Cooper, Jackie
Aoki, Junken
Kano, Kuniyuki
Humphries, Steve E.
O’Donnell, Valerie B.
author_sort Meckelmann, Sven W.
collection PubMed
description BACKGROUND: Common chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here, we applied lipidomic and genomic approaches to 3 model systems to characterize lipid metabolic changes in common Chr9p21 SNPs, which confer ≈30% elevated coronary heart disease risk associated with altered expression of ANRIL, a long ncRNA. METHODS: Untargeted and targeted lipidomics was applied to plasma from NPHSII (Northwick Park Heart Study II) homozygotes for AA or GG in rs10757274, followed by correlation and network analysis. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK-293 cells was mined. Transcriptional data from vascular smooth muscle cells differentiated from induced pluripotent stem cells of individuals with/without Chr9p21 risk, nonrisk alleles, and corresponding knockout isogenic lines were next examined. Last, an in-silico analysis of miRNAs was conducted to identify how ANRIL might control lysoPL (lysophosphospholipid)/lysoPA (lysophosphatidic acid) genes. RESULTS: Elevated risk GG correlated with reduced lysoPLs, lysoPA, and ATX (autotaxin). Five other risk SNPs did not show this phenotype. LysoPL-lysoPA interconversion was uncoupled from ATX in GG plasma, suggesting metabolic dysregulation. Significantly altered expression of several lysoPL/lysoPA metabolizing enzymes was found in HEK cells lacking ANRIL. In the vascular smooth muscle cells data set, the presence of risk alleles associated with altered expression of several lysoPL/lysoPA enzymes. Deletion of the risk locus reversed the expression of several lysoPL/lysoPA genes to nonrisk haplotype levels. Genes that were altered across both cell data sets were DGKA, MBOAT2, PLPP1, and LPL. The in-silico analysis identified 4 ANRIL-regulated miRNAs that control lysoPL genes as miR-186-3p, miR-34a-3p, miR-122-5p, and miR-34a-5p. CONCLUSIONS: A Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their metabolism. Lipid metabolites and genomic pathways associated with coronary heart disease pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.
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spelling pubmed-72992262020-06-29 Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274 Meckelmann, Sven W. Hawksworth, Jade I. White, Daniel Andrews, Robert Rodrigues, Patricia O’Connor, Anne Alvarez-Jarreta, Jorge Tyrrell, Victoria J. Hinz, Christine Zhou, You Williams, Julie Aldrovandi, Maceler Watkins, William J. Engler, Adam J. Lo Sardo, Valentina Slatter, David A. Allen, Stuart M. Acharya, Jay Mitchell, Jacquie Cooper, Jackie Aoki, Junken Kano, Kuniyuki Humphries, Steve E. O’Donnell, Valerie B. Circ Genom Precis Med Original Articles BACKGROUND: Common chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here, we applied lipidomic and genomic approaches to 3 model systems to characterize lipid metabolic changes in common Chr9p21 SNPs, which confer ≈30% elevated coronary heart disease risk associated with altered expression of ANRIL, a long ncRNA. METHODS: Untargeted and targeted lipidomics was applied to plasma from NPHSII (Northwick Park Heart Study II) homozygotes for AA or GG in rs10757274, followed by correlation and network analysis. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK-293 cells was mined. Transcriptional data from vascular smooth muscle cells differentiated from induced pluripotent stem cells of individuals with/without Chr9p21 risk, nonrisk alleles, and corresponding knockout isogenic lines were next examined. Last, an in-silico analysis of miRNAs was conducted to identify how ANRIL might control lysoPL (lysophosphospholipid)/lysoPA (lysophosphatidic acid) genes. RESULTS: Elevated risk GG correlated with reduced lysoPLs, lysoPA, and ATX (autotaxin). Five other risk SNPs did not show this phenotype. LysoPL-lysoPA interconversion was uncoupled from ATX in GG plasma, suggesting metabolic dysregulation. Significantly altered expression of several lysoPL/lysoPA metabolizing enzymes was found in HEK cells lacking ANRIL. In the vascular smooth muscle cells data set, the presence of risk alleles associated with altered expression of several lysoPL/lysoPA enzymes. Deletion of the risk locus reversed the expression of several lysoPL/lysoPA genes to nonrisk haplotype levels. Genes that were altered across both cell data sets were DGKA, MBOAT2, PLPP1, and LPL. The in-silico analysis identified 4 ANRIL-regulated miRNAs that control lysoPL genes as miR-186-3p, miR-34a-3p, miR-122-5p, and miR-34a-5p. CONCLUSIONS: A Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their metabolism. Lipid metabolites and genomic pathways associated with coronary heart disease pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated. Lippincott Williams & Wilkins 2020-05-12 /pmc/articles/PMC7299226/ /pubmed/32396387 http://dx.doi.org/10.1161/CIRCGEN.119.002806 Text en © 2020 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
spellingShingle Original Articles
Meckelmann, Sven W.
Hawksworth, Jade I.
White, Daniel
Andrews, Robert
Rodrigues, Patricia
O’Connor, Anne
Alvarez-Jarreta, Jorge
Tyrrell, Victoria J.
Hinz, Christine
Zhou, You
Williams, Julie
Aldrovandi, Maceler
Watkins, William J.
Engler, Adam J.
Lo Sardo, Valentina
Slatter, David A.
Allen, Stuart M.
Acharya, Jay
Mitchell, Jacquie
Cooper, Jackie
Aoki, Junken
Kano, Kuniyuki
Humphries, Steve E.
O’Donnell, Valerie B.
Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274
title Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274
title_full Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274
title_fullStr Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274
title_full_unstemmed Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274
title_short Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274
title_sort metabolic dysregulation of the lysophospholipid/autotaxin axis in the chromosome 9p21 gene snp rs10757274
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299226/
https://www.ncbi.nlm.nih.gov/pubmed/32396387
http://dx.doi.org/10.1161/CIRCGEN.119.002806
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