Evidence map›Paper›PMID 39240351›Full record

ArticleDiabetologia2024

Implicating type 2 diabetes effector genes in relevant metabolic cellular models using promoter-focused Capture-C.

Nicholas A Wachowski, James A Pippin, Keith Boehm, Sumei Lu, Michelle E Leonard, Elisabetta Manduchi, Ursula W Parlin, Martin Wabitsch, Alessandra Chesi, Andrew D Wells and 2 more

Abstract read
In one paragraph

Article in Diabetologia, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing 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

9 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Review
  5. Review
  6. Genetic Variants of the Human Thiamine Transporter (International journal of molecular sciences · 2025
    Article
  7. Article
  8. Article
  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

12 authors.

Nicholas A Wachowski *Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
James A Pippin *Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Keith BoehmCenter for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Sumei LuCenter for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Michelle E LeonardCenter for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Elisabetta ManduchiCenter for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Ursula W ParlinCenter for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Martin WabitschDivision of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
Alessandra ChesiDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Andrew D WellsCenter for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Struan F A Grant *Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. grants@chop.edu.
Matthew C Pahl *Center for Spatial and Functional Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Funding

Genome Wide Association Study for Childhood ObesityR01HD056465 · NICHD · CHILDREN'S HOSP OF PHILADELPHIA · PI GRANT, STRUAN F A · 2008 to 2024
$9.5M
Functional Interrogation of T2D-associated genes in human stem cell-derived models and miceUM1DK126194 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI GRANT, STRUAN F A, KAESTNER, KLAUS H · 2020 to 2024
$8.8M
Children's Hospital of Philadephia Daniel B. Burke Endowed Chair for Diabetes ResearcEunice Kennedy Shriver National Institute of Child Health and Human Development R01HD056465NICHD NIH HHS R01 HD056465NIDDK NIH HHS UM1 DK126194
6 · The paper itself

Abstract

aims/hypothesisGenome-wide association studies (GWAS) have identified hundreds of type 2 diabetes loci, with the vast majority of signals located in non-coding regions; as a consequence, it remains largely unclear which 'effector' genes these variants influence. Determining these effector genes has been hampered by the relatively challenging cellular settings in which they are hypothesised to confer their effects.

methodsTo implicate such effector genes, we elected to generate and integrate high-resolution promoter-focused Capture-C, assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA-seq datasets to characterise chromatin and expression profiles in multiple cell lines relevant to type 2 diabetes for subsequent functional follow-up analyses: EndoC-BH1 (pancreatic beta cell), HepG2 (hepatocyte) and Simpson-Golabi-Behmel syndrome (SGBS; adipocyte).

resultsThe subsequent variant-to-gene analysis implicated 810 candidate effector genes at 370 type 2 diabetes risk loci. Using partitioned linkage disequilibrium score regression, we observed enrichment for type 2 diabetes and fasting glucose GWAS loci in promoter-connected putative cis-regulatory elements in EndoC-BH1 cells as well as fasting insulin GWAS loci in SGBS cells. Moreover, as a proof of principle, when we knocked down expression of the SMCO4 gene in EndoC-BH1 cells, we observed a statistically significant increase in insulin secretion. CONCLUSIONS/

interpretationThese results provide a resource for comparing tissue-specific data in tractable cellular models as opposed to relatively challenging primary cell settings. DATA AVAILABILITY: Raw and processed next-generation sequencing data for EndoC-BH1, HepG2, SGBS_undiff and SGBS_diff cells are deposited in GEO under the Superseries accession GSE262484. Promoter-focused Capture-C data are deposited under accession GSE262496. Hi-C data are deposited under accession GSE262481. Bulk ATAC-seq data are deposited under accession GSE262479. Bulk RNA-seq data are deposited under accession GSE262480.

Indexed as

Diabetes Mellitus, Type 2Genome-Wide Association StudyPromoter Regions, GeneticCell LineHep G2 CellsHumansInsulin-Secreting CellsPolymorphism, Single NucleotideChromatin conformationEpigeneticsInsulin secretionSMCO4Type 2 diabetesVariant to gene mapping

Identifiers

PMID39240351
PMCPMC11604697

What Socratic holds

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LicenceCC BY
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Registered trials

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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 Socratic graph.