Evidence map›Paper›PMID 25164947›Full record

ArticleJournal of the American Heart Association2014

A low-frequency variant in MAPK14 provides mechanistic evidence of a link with myeloperoxidase: a prognostic cardiovascular risk marker.

Dawn M Waterworth, Li Li, Robert Scott, Liling Warren, Christopher Gillson, Jennifer Aponte, Lea Sarov-Blat, Dennis Sprecher, Josée Dupuis, Alex Reiner and 7 more

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

Article in Journal of the American Heart Association, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
0.3field-weighted citation impact, top 41% 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

3 citing papers in PubMed, 7 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
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

17 authors at 9 institutions in 3 countries.

Dawn M WaterworthGlaxoSmithKline, Philadelphia, PA (D.M.W., L.S.B., D.S.).
Li LiGlaxoSmithKline, Research Triangle Park, NC (L.L., L.W., J.A., S.C., M.G.E.).
Robert ScottMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK (R.S., C.G., N.W.).
Liling WarrenGlaxoSmithKline, Research Triangle Park, NC (L.L., L.W., J.A., S.C., M.G.E.).
Christopher GillsonMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK (R.S., C.G., N.W.).
Jennifer AponteGlaxoSmithKline, Research Triangle Park, NC (L.L., L.W., J.A., S.C., M.G.E.).
Lea Sarov-BlatGlaxoSmithKline, Philadelphia, PA (D.M.W., L.S.B., D.S.).
Dennis SprecherGlaxoSmithKline, Philadelphia, PA (D.M.W., L.S.B., D.S.).
Josée DupuisDepartment of Biostatistics, Boston University School of Public Health, Boston, MA (J.D.) Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA (J.D.).
Alex ReinerGroup Health Research Institute, Group Health Cooperative, Seattle, WA (A.R.).
Bruce M PsatyUniversity of Vermont, Burlington, VT (B.M.P.).
Russell P TracyDepartment of Medicine, Boston University School of Medicine, Boston, MA (R.P.T., H.L.).
Honghuang LinBoston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA (H.L.) Department of Medicine, Boston University School of Medicine, Boston, MA (R.P.T., H.L.).
Ruth McPhersonDivision of Cardiology and Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.P.).
Stephanie ChissoeGlaxoSmithKline, Research Triangle Park, NC (L.L., L.W., J.A., S.C., M.G.E.).
Nick WarehamMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK (R.S., C.G., N.W.).
Margaret G EhmGlaxoSmithKline, Research Triangle Park, NC (L.L., L.W., J.A., S.C., M.G.E.).
GlaxoSmithKline (United States) · USResearch Triangle Park Foundation · USBoston University · USUniversity of Cambridge · GBKaiser Permanente Washington Health Research Institute · USMRC Epidemiology Unit · GBUniversity of Ottawa · CAUniversity of Vermont · USUniversity of Washington · US

Funding

SLEEP AND ENTRAINMENT OF SCN FUNCTIONR01HL064278 · NHLBI · CASE WESTERN RESERVE UNIVERSITY · PI STROHL, KINGMAN PERKINS · 1999 to 2002
$871k
THE FRAMINGHAM HEART STUDY-N01HC25195-268025195-268025195N01HC025195 · HC · TRUSTEES OF BOSTON UNIVERSITY · PI WOLF, PHILIP A · 2002 to 2006
–
Medical Research Council MC_U106179471Medical Research Council MC_UU_12015/1NHLBI NIH HHS N01-HC-25195NHLBI NIH HHS N02-HL-6-4278
6 · The paper itself

Abstract

backgroundGenetics can be used to predict drug effects and generate hypotheses around alternative indications. To support Losmapimod, a p38 mitogen-activated protein kinase inhibitor in development for acute coronary syndrome, we characterized gene variation in MAPK11/14 genes by exome sequencing and follow-up genotyping or imputation in participants well-phenotyped for cardiovascular and metabolic traits. METHODS AND

resultsInvestigation of genetic variation in MAPK11 and MAPK14 genes using additive genetic models in linear or logistic regression with cardiovascular, metabolic, and biomarker phenotypes highlighted an association of RS2859144 in MAPK14 with myeloperoxidase in a dyslipidemic population (Genetic Epidemiology of Metabolic Syndrome Study), P=2.3×10(-6)). This variant (or proxy) was consistently associated with myeloperoxidase in the Framingham Heart Study and Cardiovascular Health Study studies (replication meta-P=0.003), leading to a meta-P value of 9.96×10(-7) in the 3 dyslipidemic groups. The variant or its proxy was then profiled in additional population-based cohorts (up to a total of 58 930 subjects) including Cohorte Lausannoise, Ely, Fenland, European Prospective Investigation of Cancer, London Life Sciences Prospective Population Study, and the Genetics of Obesity Associations study obesity case-control for up to 40 cardiovascular and metabolic traits. Overall analysis identified the same single nucleotide polymorphisms to be nominally associated consistently with glomerular filtration rate (P=0.002) and risk of obesity (body mass index ≥30 kg/m(2), P=0.004).

conclusionsAs myeloperoxidase is a prognostic marker of coronary events, the MAPK14 variant may provide a mechanistic link between p38 map kinase and these events, providing information consistent with current indication of Losmapimod for acute coronary syndrome. If replicated, the association with glomerular filtration rate, along with previous biological findings, also provides support for kidney diseases as alternative indications.

Indexed as

AdultAgedCardiovascular DiseasesDyslipidemiasExomeFemaleGenotypeHumansLinear ModelsLogistic ModelsMaleMetabolic SyndromeMiddle AgedMitogen-Activated Protein Kinase 11Mitogen-Activated Protein Kinase 14ObesityMitogen-Activated Protein Kinase 11Mitogen-Activated Protein Kinase 14Peroxidaseacute coronary syndromedrug target geneexome sequencingmyeloperoxidaserare variation

Identifiers

PMID25164947
PMCPMC4310399
OpenAlexW2166392264

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
Read underepoch 390

Registered trials

None linked

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.