Evidence map›Paper›PMID 27430239›Full record

ArticleCirculation research2016

LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis.

Wei Wang, Yang Tang, Ying Wang, Liana Tascau, Joanna Balcerek, Wei Tong, Ross L Levine, Carrie Welch, Alan R Tall, Nan Wang

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

Article in Circulation research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
52citing papers in PubMed, 2 pooled it
5.6field-weighted citation impact, top 3% 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

52 citing papers in PubMed, 2 syntheses or guidelines pooled it, 79 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Trial
  4. Article
  5. Article
  6. Article
  7. Article
  8. Article
  9. Review
  10. Review
  11. Exploring Neutrophil Extracellular Traps in Cardiovascular Pathologies: The Impact of Lipid Profiles, PAD4, and Radiation.Biocell : official journal of the Sociedades Latinoamericanas de Microscopia Electronica ... et. al · 2025
    Article
  12. Article
  13. Article
  14. Article
  15. Article
  16. Review
  17. Article
  18. Review
  19. Review
  20. A Single Nucleotide Polymorphism inCirculation research · 2022
    Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors at 2 institutions in 1 country.

Wei WangFrom the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY.
Yang TangFrom the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY.
Ying WangFrom the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY.
Liana TascauFrom the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY.
Joanna BalcerekFrom the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY.
Wei TongFrom the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY.
Ross L LevineFrom the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY.
Carrie WelchFrom the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY.
Alan R TallFrom the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY.
Nan WangFrom the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (W.W., Y.T., Y.W., L.T., C.W., A.R.T., N.W.); Division of Hematology, Children's Hospital of Philadelphia, PA (W.T.); Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (J.B., W.T.); and Human Oncology and Pathogenesis Program (R.L.L.) and Leukemia Service, Department of Medicine (R.L.L.), Memorial Sloan Kettering Cancer Center, New York, NY. nw30@columbia.edu.
Children's Hospital of Philadelphia · USUniversity of Pennsylvania · US

Funding

X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Nicholas D Socci · 1985 to 2026
$347.4M
Cholesterol efflux, CHIP and inflammasome activationR01HL107653 · NHLBI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI ALAN richard TALL · 2011 to 2026
$7.7M
Lnk Regulatory Functions in Hematopoietic Stem CellsR01HL095675 · NHLBI · CHILDREN'S HOSP OF PHILADELPHIA · PI TONG, WEI · 2009 to 2021
$5.6M
HDL, platelet progenitors, atherosclerosis and thrombosisR01HL118567 · NHLBI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI WANG, NAN · 2014 to 2018
$2.0M
BD Biosciences InfluxS10OD020056 · OD · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI SNOECK, HANS-WILLEM E · 2015 to 2015
$600k
Becton Dickinson LSR II Analytical Flow CytometerS10RR027050 · NCRR · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CLYNES, RAPHAEL A. · 2011 to 2011
$413k
NCI NIH HHS P30 CA008748NCRR NIH HHS S10 RR027050NHLBI NIH HHS R01 HL095675NHLBI NIH HHS R01 HL107653NHLBI NIH HHS R01 HL118567NIH HHS S10 OD020056
6 · The paper itself

Abstract

rationaleHuman genome-wide association studies have revealed novel genetic loci that are associated with coronary heart disease. One such locus resides in LNK/SH2B3, which in mice is expressed in hematopoietic cells and suppresses thrombopoietin signaling via its receptor myeloproliferative leukemia virus oncogene. However, the mechanisms underlying the association of LNK single-nucleotide polymorphisms with coronary heart disease are poorly understood.

objectiveTo understand the functional effects of LNK single-nucleotide polymorphisms and explore the mechanisms whereby LNK loss of function impacts atherosclerosis and thrombosis. METHODS AND

resultsUsing human cord blood, we show that the common TT risk genotype (R262W) of LNK is associated with expansion of hematopoietic stem cells and enhanced megakaryopoiesis, demonstrating reduced LNK function and increased myeloproliferative leukemia virus oncogene signaling. In mice, hematopoietic Lnk deficiency leads to accelerated arterial thrombosis and atherosclerosis, but only in the setting of hypercholesterolemia. Hypercholesterolemia acts synergistically with LNK deficiency to increase interleukin 3/granulocyte-macrophage colony-stimulating factor receptor signaling in bone marrow myeloid progenitors, whereas in platelets cholesterol loading combines with Lnk deficiency to increase activation. Platelet LNK deficiency increases myeloproliferative leukemia virus oncogene signaling and AKT activation, whereas cholesterol loading decreases SHIP-1 phosphorylation, acting convergently to increase AKT and platelet activation. Together with increased myelopoiesis, platelet activation promotes prothrombotic and proatherogenic platelet/leukocyte aggregate formation.

conclusionsLNK (R262W) is a loss-of-function variant that promotes thrombopoietin/myeloproliferative leukemia virus oncogene signaling and platelet and leukocyte production. In mice, LNK deficiency is associated with both increased platelet production and activation. Hypercholesterolemia acts in platelets and hematopoietic progenitors to exacerbate thrombosis and atherosclerosis associated with LNK deficiency.

Indexed as

Adaptor Proteins, Signal TransducingAnimalsAtherosclerosisFemaleFetal BloodGenome-Wide Association StudyHumansIntracellular Signaling Peptides and ProteinsMiceMice, Inbred C57BLMice, KnockoutPlatelet ActivationPolymorphism, Single NucleotideProteinsThrombosisAdaptor Proteins, Signal TransducingIntracellular Signaling Peptides and ProteinsProteinsSH2B3 protein, humanatherosclerosischolesterolhematopoiesishypercholesterolemiathrombosis

Identifiers

PMID27430239
PMCPMC5016083
OpenAlexW2485327755

What OpenQuestion holds

Textmetadata
LicenceTDM
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.