Evidence map›Paper›PMID 32396387›Full record

ArticleCirculation. Genomic and precision medicine2020

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

Sven W Meckelmann, Jade I Hawksworth, Daniel White, Robert Andrews, Patricia Rodrigues, Anne O'Connor, Jorge Alvarez-Jarreta, Victoria J Tyrrell, Christine Hinz, You Zhou and 14 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation. Genomic and precision medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed, 1 pooled it
1.2field-weighted citation impact, top 19% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 1 synthesis or guideline pooled it, 12 citations in OpenAlex.

  1. Effect of 9p21.3 (lncRNA and CDKN2A/2B) variant on lipid profile.Frontiers in cardiovascular medicine · 2022
    Pooled it
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  3. Review
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  6. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors at 7 institutions in 5 countries.

Sven W Meckelmann *Division of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Jade I Hawksworth *Division of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Daniel WhiteDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Robert AndrewsDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Patricia RodriguesDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Anne O'ConnorDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Jorge Alvarez-JarretaDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Victoria J TyrrellDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Christine HinzDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
You ZhouDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Julie WilliamsDivision of Neuropsychiatric Genetics and Genomics and Dementia Research Institute at Cardiff, School of Medicine (J.W.), Cardiff University, United Kingdom.
Maceler AldrovandiDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
William J WatkinsDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Adam J EnglerDepartment of Bioengineering, University of San Diego, La Jolla, CA (A.J.E.).
Valentina Lo SardoDepartment of Cellular and Molecular Neuroscience and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (V.L.S.).
David A SlatterDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Stuart M AllenSchool of Computer Science and Informatics (S.M.A.), Cardiff University, United Kingdom.
Jay AcharyaCardiovascular Genetics, Institute of Cardiovascular Science, University College London, United Kingdom (J. Acharya, J.M., J.C., S.E.H.).
Jacquie MitchellCardiovascular Genetics, Institute of Cardiovascular Science, University College London, United Kingdom (J. Acharya, J.M., J.C., S.E.H.).
Jackie CooperCardiovascular Genetics, Institute of Cardiovascular Science, University College London, United Kingdom (J. Acharya, J.M., J.C., S.E.H.).
Junken AokiSchool of Pharmaceutical Sciences, School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan (J. Aoki, K.K.).
Kuniyuki KanoSchool of Pharmaceutical Sciences, School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan (J. Aoki, K.K.).
Steve E Humphries
Valerie B O'DonnellDivision of Infection and Immunity, Systems Immunity Research Institute (S.W.M., J.I.H., D.W., R.A., P.R., A.O., J.A.-J., V.J.T., C.H., Y.Z., M.A., W.J.W., D.A.S., V.B.O.), Cardiff University, United Kingdom.
Institute of Infection and Immunity · CACardiovascular Institute of the South · USTohoku Medical and Pharmaceutical University · JPCardiff University · GBLa Jolla Bioengineering Institute · USScripps Research Institute · USUK Dementia Research Institute · GB

Funding

British Heart Foundation RG008/08British Heart Foundation RG/12/11/29815European Research Council 339129Medical Research Council MR/L010305/1Wellcome Trust 094143/Z/10/ZWellcome Trust 203014/Z/16/Z
6 · The paper itself

Abstract

backgroundCommon 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.

methodsUntargeted 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.

resultsElevated 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

conclusionsA 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.

Indexed as

Coronary DiseaseLysophospholipidsPhosphoric Diester HydrolasesPolymorphism, Single NucleotideChromosomes, Human, Pair 9HEK293 CellsHumansLysophospholipase DMaleMiddle Agedlysophosphatidic acidLysophospholipase DLysophospholipidsPhosphoric Diester Hydrolasesatherosclerosislipidsmass spectrometryphenotypephospholipids

Identifiers

PMID32396387
PMCPMC7299226
OpenAlexW3024646306

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.