Evidence map›Paper›PMID 39626097›Full record

ArticleDiabetes care2025

Genetic Discovery and Risk Prediction for Type 1 Diabetes in Individuals Without High-Risk HLA-DR3/DR4 Haplotypes.

Carolyn McGrail, Joshua Chiou, Ruth Elgamal, Amber M Luckett, Richard A Oram, Paola Benaglio, Kyle J Gaulton

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Diabetes care, 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. Article
  2. Article
  3. Review
  4. Review
  5. Article
  6. Review
  7. Type 1 Diabetes Genetics Consortium.The Journal of clinical endocrinology and metabolism · 2025
    Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

7 authors.

Carolyn McGrailBiomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA.
Joshua ChiouBiomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA.
Ruth ElgamalBiomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA.
Amber M LuckettUniversity of Exeter College of Medicine and Health, Exeter, U.K.ORCID 0000-0001-9496-3796
Richard A OramUniversity of Exeter College of Medicine and Health, Exeter, U.K.ORCID 0000-0003-3581-8980
Paola BenaglioDepartment of Pediatrics, University of California, San Diego, La Jolla, CA.
Kyle J GaultonDepartment of Pediatrics, University of California, San Diego, La Jolla, CA.ORCID 0000-0003-1318-7161

Funding

Type 1 Diabetes Genetics ConsortiumU01DK062418 · NIDDK · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI RICH, STEPHEN S. · 2002 to 2007
$59.8M
Furthering scientific understanding of mechanisms underlying resilience to the effects of AD pathology by incorporating state of the art quantification of gliosis, inflammation, & synaptic toxicityU01AG006781 · NIA · UNIVERSITY OF WASHINGTON · PI CRANE, PAUL K, LARSON, ERIC B · 1986 to 2020
$39.3M
JH/CIDR Genotyping for Genome-Wide Association StudiesU01HG004438 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2007 to 2011
$24.2M
A Center for GEI Association StudiesU01HG004424 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY · 2007 to 2010
$21.4M
Neurodevelopmental Genomics: Trajectories of Complex PhenotypesRC2MH089983 · NIMH · UNIVERSITY OF PENNSYLVANIA · PI GUR, RAQUEL E · 2009 to 2011
$14.3M
2/2 Neurodevelopmental Genomics: Trajectories of Complex PhenotypesRC2MH089924 · NIMH · CHILDREN'S HOSP OF PHILADELPHIA · PI HAKONARSON, HAKON · 2009 to 2011
$10.7M
MOLECULAR GENETICS OF SCHIZOPHRENIAR01MH059571 · NIMH · UNIVERSITY OF CHICAGO · PI GEJMAN, PABLO V. · 1999 to 2007
$8.0M
Vanderbilt Genome-Electronic Records ProjectU01HG004603 · NHGRI · VANDERBILT UNIVERSITY · PI RODEN, DAN M · 2007 to 2011
$7.3M
Genetic mechanisms of type 1 diabetes risk in stress-induced pancreatic isletsR01DK122607 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GAULTON, KYLE JEFFRIE · 2019 to 2022
$4.4M
A Genome-Wide Association Study of SchizophreniaU01MH079469 · NIMH · NORTHSHORE UNIVERSITY HEALTHSYSTEM · PI GEJMAN, PABLO V. · 2007 to 2009
$4.4M
Development and Use of Network Infrastructure for High-Throughput GWA StudiesU01HG004610 · NHGRI · KAISER FOUNDATION HEALTH PLAN OF WASHINGTON · PI LARSON, ERIC B · 2007 to 2010
$4.2M
EMR Phenotypes and Community Engaged Genomic AssociationsU01HG004599 · NHGRI · MAYO CLINIC ROCHESTER · PI CHUTE, CHRISTOPHER G · 2007 to 2010
$3.7M
Division of Diabetes, Endocrinology, and Metabolic Diseases DK120429NHGRI NIH HHS U01 HG004424NHGRI NIH HHS U01 HG004438NHGRI NIH HHS U01 HG004599NHGRI NIH HHS U01 HG004603NHGRI NIH HHS U01 HG004608NHGRI NIH HHS U01 HG004609NHGRI NIH HHS U01 HG004610NHLBI NIH HHS R01 HL075794NIA NIH HHS U01 AG006781NIDDK NIH HHS R01 DK122607NIDDK NIH HHS U01 DK062418NIDDK NIH HHS U01 DK120429NIMH NIH HHS R01 MH059565NIMH NIH HHS R01 MH059566NIMH NIH HHS R01 MH059571NIMH NIH HHS R01 MH059586NIMH NIH HHS R01 MH059587NIMH NIH HHS R01 MH059588NIMH NIH HHS R01 MH060870NIMH NIH HHS R01 MH060879NIMH NIH HHS R01 MH061675NIMH NIH HHS R01 MH067257NIMH NIH HHS R01 MH081800NIMH NIH HHS RC2 MH089924NIMH NIH HHS RC2 MH089983NIMH NIH HHS U01 MH046276NIMH NIH HHS U01 MH046318NIMH NIH HHS U01 MH079469NIMH NIH HHS U01 MH079470Wellcome Trust
6 · The paper itself

Abstract

objectiveMore than 10% of patients with type 1 diabetes (T1D) do not have high-risk HLA-DR3 or -DR4 haplotypes with distinct clinical features, such as later onset and reduced insulin dependence. We aimed to identify genetic drivers of T1D in the absence of DR3/DR4 and improve prediction of T1D risk in these individuals. RESEARCH DESIGN AND

methodsWe performed T1D association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Next, we performed heterogeneity tests to examine differences in T1D risk variants in individuals without versus those with DR3/DR4 haplotypes. We further assessed genome-wide differences in gene regulatory element and biological pathway enrichments between the non-DR3/DR4 and DR3/DR4 cohorts. Finally, we developed a genetic risk score (GRS) to predict T1D in individuals without DR3/DR4 and compared with an existing T1D GRS.

resultsA total of 18 T1D risk variants in non-DR3/DR4 samples were identified. Risk variants at the MHC and multiple other loci genome wide had heterogeneity in effects on T1D dependent on DR3/DR4 status, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-associated variants in non-DR3/DR4 were more enriched for regulatory elements and pathways involved in antigen presentation, innate immunity, and β-cells and depleted in T cells compared with DR3/DR4. A non-DR3/DR4 GRS outperformed an existing risk score GRS2 in discriminating non-DR3/DR4 T1D from no diabetes (area under the curve 0.867; P = 7.48 × 10-32) and type 2 diabetes (0.907; P = 4.94 × 10-44).

conclusionsIn total, we identified heterogeneity in T1D genetic risk dependent on high-risk HLA-DR3/DR4 haplotype, which uncovers disease mechanisms and enables more accurate prediction of T1D across the HLA background.

Indexed as

Diabetes Mellitus, Type 1HLA-DR3 AntigenHLA-DR4 AntigenFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyHaplotypesHumansPolymorphism, Single NucleotideHLA-DR3 AntigenHLA-DR4 Antigen

Identifiers

PMID39626097
PMCPMC11770152

What Socratic holds

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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.