Evidence map›Paper›PMID 27159840›Full record

ArticleArthritis & rheumatology (Hoboken, N.J.)2016

LBH Gene Transcription Regulation by the Interplay of an Enhancer Risk Allele and DNA Methylation in Rheumatoid Arthritis.

Deepa Hammaker, John W Whitaker, Keisuke Maeshima, David L Boyle, Anna-Karin H Ekwall, Wei Wang, Gary S Firestein

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

Article in Arthritis & rheumatology (Hoboken, N.J.), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed, 1 pooled it
6.1field-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

26 citing papers in PubMed, 1 synthesis or guideline pooled it, 42 citations in OpenAlex.

  1. Pooled it
  2. Review
  3. DNA hypomethylation ameliorates erosive inflammatory arthritis by modulating interferon regulatory factor-8.Proceedings of the National Academy of Sciences of the United States of America · 2024
    Article
  4. Article
  5. Celiac disease: From genetics to epigenetics.World journal of gastroenterology · 2022
    Review
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  7. Review
  8. Observational
  9. Review
  10. Review
  11. Review
  12. Article
  13. Article
  14. Review
  15. Fine-mappingeLife · 2019
    Article
  16. Review
  17. Article
  18. Review
  19. Article
  20. 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

7 authors at 2 institutions in 2 countries.

Deepa HammakerUniversity of California at San Diego, La Jolla.
John W WhitakerUniversity of California at San Diego, La Jolla.
Keisuke MaeshimaUniversity of California at San Diego, La Jolla.
David L BoyleUniversity of California at San Diego, La Jolla.
Anna-Karin H EkwallAnna-Karin H. Ekwall, MD, PhD: The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Wei WangUniversity of California at San Diego, La Jolla.
Gary S FiresteinUniversity of California at San Diego, La Jolla. transmed@ucsd.edu.
University of California, San Diego · USUniversity of Gothenburg · SE

Funding

Identification of key regulators in rheumatoid arthritisR01AR065466 · NIAMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI FIRESTEIN, GARY S, WANG, WEI · 2014 to 2024
$4.6M
NIAMS NIH HHS R01 AR065466
6 · The paper itself

Abstract

objectiveTo identify nonobvious therapeutic targets for rheumatoid arthritis (RA), we performed an integrative analysis incorporating multiple "omics" data and the Encyclopedia of DNA Elements (ENCODE) database for potential regulatory regions. This analysis identified the limb bud and heart development (LBH) gene, which has risk alleles associated with RA/celiac disease and lupus, and can regulate cell proliferation in RA. We identified a novel LBH transcription enhancer with an RA risk allele (rs906868 G [Ref]/T) 6 kb upstream of the LBH gene with a differentially methylated locus. The confluence of 3 regulatory elements, rs906868, an RA differentially methylated locus, and a putative enhancer, led us to investigate their effects on LBH regulation in fibroblast-like synoviocytes (FLS).

methodsWe cloned the 1.4-kb putative enhancer with either the rs906868 Ref allele or single-nucleotide polymorphism (SNP) variant into reporter constructs. The constructs were methylated in vitro and transfected into cultured FLS by nucleofection.

resultsWe found that both variants increased transcription, thereby confirming the region's enhancer function. Unexpectedly, the transcriptional activity of the Ref risk allele was significantly lower than that of the SNP variant and is consistent with low LBH levels as a risk factor for aggressive FLS behavior. Using RA FLS lines with a homozygous Ref or SNP allele, we confirmed that homozygous Ref lines expressed lower LBH messenger RNA levels than did the SNP lines. Methylation significantly reduced enhancer activity for both alleles, indicating that enhancer function is dependent on its methylation status.

conclusionThis study shows how the interplay between genetics and epigenetics can affect expression of LBH in RA.

Indexed as

Arthritis, RheumatoidCells, CulturedChromatin ImmunoprecipitationDNA MethylationEpigenesis, GeneticHomozygoteHumansIsoantigensMutationPolymorphism, Single NucleotideReal-Time Polymerase Chain ReactionRisk FactorsRNA, MessengerSeminal Plasma ProteinsSynoviocytesTrans-ActivatorsIsoantigensLBH protein, humanRNA, MessengerSeminal Plasma ProteinsSPACA3 protein, humanTrans-ActivatorsTranscription Factors

Identifiers

PMID27159840
PMCPMC5083131
OpenAlexW2545267365

What OpenQuestion holds

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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.