Evidence map›Paper›PMID 40119478›Full record

ArticleGenome medicine2025

Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.

Marios K Georgakis, Rainer Malik, Omar El Bounkari, Natalie R Hasbani, Jiang Li, Jennifer E Huffman, Gabrielle Shakt, Reinier W P Tack, Tamara N Kimball, Yaw Asare and 55 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genome medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
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

7 citing papers in PubMed.

  1. Review
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  3. Monocyte Chemokines Enhance Atherosclerotic Plaque Necrosis After Bacterial Kidney Infection.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026
    Article
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

65 authors.

Marios K Georgakis *Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Feodor-Lynen-Str. 17, 81377, Munich, Germany. marios.georgakis@med.uni-muenchen.de.
Rainer Malik *Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Feodor-Lynen-Str. 17, 81377, Munich, Germany.
Omar El BounkariInstitute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Feodor-Lynen-Str. 17, 81377, Munich, Germany.
Natalie R HasbaniHuman Genetics Center, Department of Epidemiology, School of Public Health, Human Genetics, and Environmental Sciences, the University of Texas Health Science Center at Houston, Houston, TX, USA.
Jiang LiDepartment of Molecular and Functional Genomics, Geisinger Health System, Danville, PA, USA.
Jennifer E HuffmanVeterans Affairs Healthcare System, Boston, MA, USA.
Gabrielle ShaktDepartment of Surgery, Perelman School of Medicineat Theaq , University of Pennsylvania, Philadelphia, PA, USA.
Reinier W P TackProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Tamara N KimballProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Yaw AsareInstitute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Feodor-Lynen-Str. 17, 81377, Munich, Germany.
Alanna C MorrisonHuman Genetics Center, Department of Epidemiology, School of Public Health, Human Genetics, and Environmental Sciences, the University of Texas Health Science Center at Houston, Houston, TX, USA.
Noah L TsaoDepartment of Surgery, Perelman School of Medicineat Theaq , University of Pennsylvania, Philadelphia, PA, USA.
Renae JudyDepartment of Surgery, Perelman School of Medicineat Theaq , University of Pennsylvania, Philadelphia, PA, USA.
Braxton D MitchellDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Huichun XuDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
May E MontasserDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Ron DoThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Eimear E KennyThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ruth J F LoosThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
James G TerryDepartment of Radiology, Vanderbilt University Medical Center, Nashville, TN, USA.
John Jeffrey CarrDepartment of Radiology, Vanderbilt University Medical Center, Nashville, TN, USA.
Joshua C BisDepartment of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
Bruce M PsatyDepartment of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
W T LongstrethDepartment of Epidemiology, University of Washington, Seattle, WA, USA.
Kendra A YoungDepartment of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Sharon M LutzDepartment of Population Medicine, PRecisiOn Medicine Translational Research (PROMoTeR) Center, Harvard Pilgrim Health Careand, Harvard Medical School , Boston, MA, USA.
Michael H ChoChanning Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jai BroomeDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
Alyna T KhanDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
Fei Fei WangDepartment of Biostatistics, University of Washington, Seattle, WA, USA.
Nancy Heard-CostaDepartment of Medicine, Boston University School of Medicine, Boston, MA, USA.
Sudha SeshadriBigg'S Institute for Alzheimer'S Disease and Neurodegenerative Disorders, University of Texas Health Science Center, San Antonio, TX, USA.
Ramachandran S VasanDepartment of Medicine, Boston University School of Medicine, Boston, MA, USA.
Nicholette D PalmerDepartment of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Barry I FreedmanSection on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Donald W BowdenDepartment of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Lisa R YanekDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Brian G KralDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Lewis C BeckerDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Patricia A PeyserDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Lawrence F BielakDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Farah AmmousDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
April P CarsonDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
Michael E HallDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
Laura M RaffieldDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Wendy S PostJohns Hopkins Bloomberg School of Public Health, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Russel P TracyDepartments of Pathology & Laboratory Medicine, and Biochemistry, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Kent D TaylorThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Xiuqing GuoThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Michael C MahaneyDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
Joanne E CurranDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
John BlangeroDepartment of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
Shoa L ClarkeDepartment of Medicine (Division of Cardiovascular Medicine), Stanford University School of Medicine, Stanford, CA, USA.
Jeffrey W HaesslerDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
Yao HuDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
Themistocles L AssimesDepartment of Medicine (Division of Cardiovascular Medicine), Stanford University School of Medicine, Stanford, CA, USA.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
Jürgen BernhagenInstitute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Feodor-Lynen-Str. 17, 81377, Munich, Germany.
Christopher D AndersonProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Scott M DamrauerDepartment of Surgery, Perelman School of Medicineat Theaq , University of Pennsylvania, Philadelphia, PA, USA.
Ramin ZandDepartment of Neurology, Pennsylvania State University, Hershey, PA, USA.
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Paul S de VriesHuman Genetics Center, Department of Epidemiology, School of Public Health, Human Genetics, and Environmental Sciences, the University of Texas Health Science Center at Houston, Houston, TX, USA.
Martin DichgansInstitute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Feodor-Lynen-Str. 17, 81377, Munich, Germany. martin.dichgans@med.uni-muenchen.de.

Funding

Workforce Development CoreU54HG013247 · NHGRI · UNIVERSITY OF TEXAS RIO GRANDE VALLEY · PI John Blangero · 2023 to 2026
$10.5M
CHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5M
SOLAR-Eclipse Computational Tools for Imaging GeneticsR01EB015611 · NIBIB · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI KOCHUNOV, PETER V. · 2012 to 2024
$5.0M
The role of sex in genetic association studies of depressionR01MH129337 · NIMH · HARVARD PILGRIM HEALTH CARE, INC. · PI Sharon Marie Lutz · 2022 to 2026
$2.1M
NHGRI NIH HHS U54 HG013247NHLBI NIH HHS R01 HL105756NIBIB NIH HHS R01 EB015611NIMH NIH HHS R01 MH129337
6 · The paper itself

Abstract

backgroundPrevious work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

methodsComputationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595).

resultsCarriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95% confidence interval [CI]: 0.54-0.81, p = 6.1 × 10

conclusionsCarriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

Indexed as

Cardiovascular DiseasesGenetic Predisposition to DiseaseGenetic VariationReceptors, CCR2AgedChemokine CCL2FemaleHumansMaleMiddle AgedMonocytesRisk FactorsCCR2 protein, humanChemokine CCL2Receptors, CCR2AtherosclerosisCardiovascular diseaseCCR2GeneticsInflammation

Identifiers

PMID40119478
PMCPMC11929344

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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.