Evidence map›Paper›PMID 40480020›Full record

ArticleAtherosclerosis2025

Epigenetic mechanisms underlying variation of IL-6, a well-established inflammation biomarker and risk factor for cardiovascular disease.

Jessica I Lundin, Ulrike Peters, Yao Hu, Farah Ammous, Emelia J Benjamin, Joshua C Bis, Jennifer A Brody, Mary Cushman, Harriett Fuller, Chris Gignoux and 27 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Atherosclerosis, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed, 1 pooled it
–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

8 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Review
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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

37 authors.

Jessica I LundinDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. Electronic address: Jlundin2@fredhutch.org.
Ulrike PetersDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA. Electronic address: upeters@fredhutch.org.
Yao HuDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. Electronic address: yhu23@fredhutch.org.
Farah AmmousSurvey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA. Electronic address: fammous@umich.edu.
Emelia J BenjaminBoston Medical Center, Boston University Chobanian and Avedisian School of Medicine, Boston University School of Public Health, Boston, MA, USA. Electronic address: emelia@bu.edu.
Joshua C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA. Electronic address: joshbis@uw.edu.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA. Electronic address: jeco@uw.edu.
Mary CushmanDepartment of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, USA. Electronic address: mary.cushman@uvm.edu.
Harriett FullerDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. Electronic address: hfuller@fredhutch.org.
Chris GignouxQuantitative Biology, University of Colorado, Boulder, CO, USA. Electronic address: chris.gignoux@cuanschutz.edu.
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. Electronic address: xguo@lundquist.org.
Jeff HaesslerDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. Electronic address: jhaessle@WHI.org.
Chris HaimanKeck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: christopher.haiman@med.usc.edu.
Roby JoehanesPopulation Sciences Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, USA; Framingham Heart Study, Framingham, MA, USA. Electronic address: roby.joehanes@nih.gov.
Silva KaselaNew York Genome Center, New York, NY, USA. Electronic address: silva.kasela@gmail.com.
Eimear KennyIcahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: eimear.kenny@mssm.edu.
Tuuli LappalainenNew York Genome Center, New York, NY, USA. Electronic address: tlappalainen@nygenome.org.
Daniel LevyPopulation Sciences Branch, National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, MD, USA. Electronic address: levyd@nhlbi.nih.gov.
Chunyu LiuDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA. Electronic address: liuc@bu.edu.
Yongmei LiuDuke Molecular Physiology Institute, Duke University, Durham, NC, USA. Electronic address: yongmei.liu@duke.edu.
Ruth J F LoosIcahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: ruth.loos@mssm.edu.
Tara MatiseDepartment of Genetics, Rutgers University, New Brunswick, NJ, USA. Electronic address: matise@rutgers.edu.
Kari E NorthDepartment of Epidemiology, University of North Carolina, Chapel Hill, NC, USA. Electronic address: kari_north@unc.edu.
Sungshim L ParkEpidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA. Electronic address: lpark@cc.hawaii.edu.
Scott M RatliffDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA. Electronic address: ratliffs@umich.edu.
Alex ReinerDepartment of Epidemiology, University of Washington, Seattle, WA, USA. Electronic address: apreiner@uw.edu.
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. Electronic address: ssr4n@virginia.edu.
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. Electronic address: jrotter@lundquist.org.
Jennifer A SmithSurvey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA; Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA. Electronic address: smjenn@umich.edu.
Nona SotoodehniaCardiovascular Health Research Unit, Harborview Medical Center, Seattle, WA, USA. Electronic address: nsotoo@uw.edu.
Russell TracyDepartment of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, USA. Electronic address: Russell.Tracy@uvm.edu.
David Van den BergKeck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address: dvandenb@usc.edu.
Ting YeDepartment of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA. Electronic address: tingye1@uw.edu.
Wei ZhaoSurvey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA. Electronic address: zhaowei@umich.edu.
Laura M RaffieldDepartment of Genetics, University of North Carolina, Chapel Hill, NC, USA. Electronic address: laura_raffield@unc.edu.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. Electronic address: clk@fredhutch.org.
PAGE Study

Funding

Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6M
UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1M
Institute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1M
UCLA Clinical and Translational Science InstituteUL1TR000124 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DUBINETT, STEVEN M. · 2012 to 2015
$57.0M
WOMEN'S HEALTH INITIATIVE - CLINICAL COORDINATING CENTER: TASK AREA B - LONG LIFE STUDY VISIT 2 LIMITED HOME VISIT75N92021D00001 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI ANDERSON, GARNET L. · 2021 to 2025
$52.0M
Transgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MILES Frome WILKINSON · 2003 to 2026
$40.4M
Wake Forest Clinical and Translational Science AwardUL1TR001420 · NCATS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ARD, JAMY D, FOLEY, KRISTIE L · 2015 to 2023
$32.3M
FRAMINGHAM HEART STUDY - YEAR 5 EXAM75N92019D00031 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · 2019 to 2024
$29.8M
Clinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2M
IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVALR01HL092577 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI BENJAMIN, EMELIA J., ELLINOR, PATRICK THOMAS · 2009 to 2025
$20.6M
Task Area A Core Study Operations.Task Area A shall encompass annual follow-up of cohort members, clinical endpoints ascertainment, study coordination activities, maintenance of the database and biosp75N92020D00001 · NHLBI · UNIVERSITY OF WASHINGTON · PI MCCLELLAND, ROBYN LEAGH · 2020 to 2025
$17.2M
Studies of Rare Genetic Variation in the Isolated Population of SardiniaR01HL117626 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2013 to 2016
$10.5M
NCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR000124NCATS NIH HHS UL1 TR001079NCATS NIH HHS UL1 TR001420NCATS NIH HHS UL1 TR001881NHGRI NIH HHS R01 HG010297NHGRI NIH HHS U54 HG003067NHLBI NIH HHS 75N92019D00031NHLBI NIH HHS 75N92020D00001NHLBI NIH HHS 75N92020D00002NHLBI NIH HHS 75N92020D00003NHLBI NIH HHS 75N92020D00004NHLBI NIH HHS 75N92020D00005NHLBI NIH HHS 75N92020D00006NHLBI NIH HHS 75N92020D00007NHLBI NIH HHS 75N92021D00001NHLBI NIH HHS 75N92021D00002NHLBI NIH HHS 75N92021D00006NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HHSN268201500001CNHLBI NIH HHS HHSN268201500001INHLBI NIH HHS HHSN268201500003CNHLBI NIH HHS HHSN268201500003INHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS K08 HL116640NHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI NIH HHS N01 HC085083NHLBI NIH HHS N01 HC085086NHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095160NHLBI NIH HHS N01 HC095161NHLBI NIH HHS N01 HC095162NHLBI NIH HHS N01 HC095163NHLBI NIH HHS N01 HC095164NHLBI NIH HHS N01 HC095165NHLBI NIH HHS N01 HC095166NHLBI NIH HHS N01 HC095167NHLBI NIH HHS N01 HC095168NHLBI NIH HHS N01 HC095169NHLBI NIH HHS R01 HL076784NHLBI NIH HHS R01 HL087652NHLBI NIH HHS R01 HL092111NHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL103612NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL111089NHLBI NIH HHS R01 HL116747NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL142302NHLBI NIH HHS R01 HL172803NHLBI NIH HHS U01 HL080295NHLBI NIH HHS U01 HL120393NHLBI NIH HHS U01 HL130114NIA NIH HHS R01 AG023629NIA NIH HHS R01 AG028321NIDDK NIH HHS P30 DK063491NIH HHS S10 OD028685WHI NIH HHS 75N92021D00003WHI NIH HHS 75N92021D00004WHI NIH HHS 75N92021D00005
6 · The paper itself

Abstract

BACKGROUND AND

aimsCardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, yet the underlying molecular mechanisms remain less understood. Chronic low-grade inflammation is a complex immune response contributing to the pathophysiology of cardiovascular disease. This response is signaled in part by interleukin-6 (IL-6), a pleiotropic, pro-inflammatory cytokine. Phenotypic variance in circulating IL-6 level may be explained in part by DNA methylation which is increasingly being associated with cardiovascular effects.

methodsIn this study we evaluated methylated DNA (CpG sites) associated with blood IL-6 levels across ∼4,400 ancestrally diverse individuals (81 % self-reported White; 9 % Black or African American, 8 % Hispanic or Latino/a, and 2 % Chinese American).

resultsWe identified 178 CpG sites associated with IL-6 (p<0.05/∼395,000). Among the sites, cg04437762 is located within the transcription unit of IL6R, a current therapeutic target for inflammatory disease, and cg26692003 and cg00464927 were significant for IL6 and IL6ST trans-CpG-gene transcripts. Functional gene expression downstream of methylation identified cellular response to IL-6 and B-cell regulation and activation pathways. Four genes were linked with both a genetic component of cardiovascular disease and an IL-6 associated CpG site. Three CpG sites identified through Mendelian randomization analyses supported inference of a causal effect on IL-6 levels, including the LYN gene that regulates immune cell signaling and has been previously associated with atherosclerosis.

conclusionsOverall, we identified several novel IL-6-CpG sites and downstream pathways affected by methylation. Follow-up functional studies including the regulation of IL-6 would complement current knowledge of CVD pathophysiology and potential therapeutic targets.

Indexed as

Cardiovascular DiseasesDNA MethylationEpigenesis, GeneticInflammationInterleukin-6BiomarkersCpG IslandsCytokine Receptor gp130FemaleGenetic Predisposition to DiseaseHeart Disease Risk FactorsHumansMaleMiddle AgedReceptors, Interleukin-6Risk FactorsBiomarkersCytokine Receptor gp130IL6 protein, humanIL6R protein, humanIL6ST protein, humanInterleukin-6Receptors, Interleukin-6

Identifiers

PMID40480020
PMCPMC12276907

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