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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 ORCID:, Alvarez-Jarreta, Jorge, Tyrrell, Victoria J., Hinz, Christine, Zhou, You ORCID:, Williams, Julie ORCID:, Aldrovandi, Maceler, Watkins, William J. ORCID:, Engler, Adam J., Lo Sardo, Valentina, Slatter, David A., Allen, Stuart M. ORCID:, Acharya, Jay, Mitchell, Jacquie, Cooper, Jackie, Aoki, Junken, Kano, Kuniyuki, Humphries, Steve E. and O'Donnell, Valerie B. ORCID: 2020. Metabolic dysregulation of the lysophospholipid/autotaxin axis in the chromosome 9p21 gene SNP rs10757274. Circulation: Genomic and Precision Medicine 13 (3) , pp. 149-164. 10.1161/CIRCGEN.119.002806

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Background - Common chromosome 9p21 SNPs increase coronary heart disease (CHD) 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 three model systems, to characterize lipid metabolic changes in common Chr9p21 SNPs which confer ~30% elevated CHD risk associated with altered expression of ANRIL, a long ncRNA. Methods - Untargeted and targeted lipidomics was applied to plasma from Northwick Park Heart Study II (NPHSII) 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 HEK293 cells was mined. Transcriptional data from vascular smooth muscle cells differentiated from iPSCs of individuals with/without Chr9p21 risk, non-risk 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/lysoPA genes. Results - Elevated risk GG correlated with reduced lysophosphospholipids (lysoPLs), lysophosphatidic acids (lysoPA) and autotaxin (ATX). 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 metabolising enzymes was found in HEK cells lacking ANRIL. In the VSMC dataset, the presence of risk alleles associated with altered expression of several lysoPL/lysoPA enzymes. Deletion of the risk locus reversed expression of several lysoPL/lysoPA genes to non-risk haplotype levels. Genes that were altered across both cell datasets were DGKA, MBOAT2, PLPP1 and LPL. The in-silico analysis identified four ANRIL-regulated miRNAs that control lysoPL genes as miR-186-3p, miR-34a-3p, miR-122-5p, 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 CHD pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Publisher: American Heart Association
ISSN: 2574-8300
Funders: Wellcome Trust
Date of First Compliant Deposit: 20 May 2020
Date of Acceptance: 12 March 2020
Last Modified: 10 Nov 2023 02:06

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