Evidence map›Paper›PMID 33369221›Full record

ArticleArthritis & rheumatology (Hoboken, N.J.)2021

Functional Genomic Analysis of a RUNX3 Polymorphism Associated With Ankylosing Spondylitis.

Matteo Vecellio, Liye Chen, Carla J Cohen, Adrian Cortes, Yan Li, Sarah Bonham, Carlo Selmi, Matthew A Brown, Roman Fischer, Julian C Knight and 1 more

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

Article in Arthritis & rheumatology (Hoboken, N.J.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed, 1 pooled it
1.9field-weighted citation impact, top 13% 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

9 citing papers in PubMed, 1 synthesis or guideline pooled it, 15 citations in OpenAlex.

  1. Pooled it
  2. TOPK Suppresses the CD8Cancer communications (London, England) · 2026
    Article
  3. Evolving role of CD8Frontiers in immunology · 2026
    Review
  4. Article
  5. Article
  6. Article
  7. Review
  8. Review
  9. 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

11 authors at 6 institutions in 4 countries.

Matteo VecellioNIHR Oxford Musculoskeletal Biomedical Research Unit, Botnar Research Centre, Nuffield Orthopaedic Centre, NIHR Oxford Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK.ORCID 0000-0002-8643-1316
Liye ChenNIHR Oxford Musculoskeletal Biomedical Research Unit, Botnar Research Centre, Nuffield Orthopaedic Centre, NIHR Oxford Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK.
Carla J CohenNIHR Oxford Musculoskeletal Biomedical Research Unit, Botnar Research Centre, Nuffield Orthopaedic Centre, NIHR Oxford Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK.
Adrian CortesJohn Radcliffe Hospital, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Yan LiThe First Affiliated Hospital of Xiamen University and Xiamen University School of Medicine, Xiamen, China.
Sarah BonhamTarget Discovery Institute, University of Oxford, Oxford, UK.
Carlo SelmiIRCCS Humanitas Research Hospital, Milan, Italy.
Matthew A BrownNIHR Guy's and St. Thomas' Biomedical Research Centre, London, UK, and University of Queensland, Brisbane, Queensland, Australia.
Roman FischerTarget Discovery Institute, University of Oxford, Oxford, UK.
Julian C KnightWellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
B Paul WordsworthNIHR Oxford Musculoskeletal Biomedical Research Unit, Botnar Research Centre, Nuffield Orthopaedic Centre, NIHR Oxford Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK.
Nuffield Orthopaedic Centre · GBCentre for Human Genetics · GBUniversity of Oxford · GBFirst Affiliated Hospital of Xiamen University · CNIRCCS Humanitas Research Hospital · ITThe University of Queensland · AU

Funding

Versus Arthritis 20402Versus Arthritis 20773Versus Arthritis 20796Versus Arthritis 21428Versus Arthritis 22053
6 · The paper itself

Abstract

objectiveTo investigate the functional consequences of the single-nucleotide polymorphism rs4648889 in a putative enhancer upstream of the RUNX3 promoter associated with susceptibility to ankylosing spondylitis (AS).

methodsUsing nuclear extracts from Jurkat cells and primary human CD8+ T cells, the effects of rs4648889 on allele-specific transcription factor (TF) binding were investigated by DNA pull-down assay and quantitative mass spectrometry (qMS), with validation by electrophoretic mobility shift assay (EMSA), Western blotting of the pulled-down eluates, and chromatin immunoprecipitation (ChIP)-quantitative polymerase chain reaction (qPCR) analysis. Further functional effects were tested by small interfering RNA knockdown of the gene for interferon regulatory factor 5 (IRF5), followed by reverse transcription-qPCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) to measure the levels of IFNγ messenger RNA (mRNA) and protein, respectively.

resultsIn nuclear extracts from CD8+ T cells, results of qMS showed that relative TF binding to the AS-risk A allele of rs4648889 was increased 3.7-fold (P < 0.03) for Ikaros family zinc-finger protein 3 (IKZF3; Aiolos) and components of the NuRD complex, including chromodomain helicase DNA binding protein 4 (CHD4) (3.6-fold increase; P < 0.05) and retinoblastoma binding protein 4 (RBBP4) (4.1-fold increase; P < 0.03). In contrast, IRF5 bound significantly more to the AS-protective G allele compared to the AS-risk A allele (fold change 8.2; P = 0.003). Validation with Western blotting, EMSA, and ChIP-qPCR confirmed the differential allelic binding of IKZF3, CHD4, RBBP4, and IRF5. Silencing of IRF5 in CD8+ T cells increased the levels of IFNγ mRNA as measured by RT-qPCR (P = 0.03) and IFNγ protein as measured by ELISA (P = 0.02).

conclusionThese findings suggest that the association of rs4648889 with AS reflects allele-specific binding of this enhancer-like region to certain TFs, including IRF5, IKZF3, and members of the NuRD complex. IRF5 may have crucial influences on the functions of CD8+ lymphocytes, a finding that could reveal new therapeutic targets for the management of AS.

Indexed as

Blotting, WesternCD8-Positive T-LymphocytesCore Binding Factor Alpha 3 SubunitElectrophoretic Mobility Shift AssayEnzyme-Linked Immunosorbent AssayGene Expression RegulationGene Knockdown TechniquesGenetic Predisposition to DiseaseHumansIkaros Transcription FactorInterferon-gammaInterferon Regulatory FactorsJurkat CellsMass SpectrometryMi-2 Nucleosome Remodeling and Deacetylase ComplexPolymorphism, Single NucleotideCHD4 protein, humanCore Binding Factor Alpha 3 SubunitIFNG protein, humanIkaros Transcription FactorIKZF3 protein, humanInterferon-gammaInterferon Regulatory FactorsIRF5 protein, humanMi-2 Nucleosome Remodeling and Deacetylase ComplexRBBP4 protein, humanRetinoblastoma-Binding Protein 4RNA, MessengerRNA, Small InterferingRunx3 protein, humanTranscription Factors

Identifiers

PMID33369221
PMCPMC8251554
OpenAlexW3117043196

What OpenQuestion holds

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LicenceCC BY
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.