Novel diabetes gene discovery through comprehensive characterization and integrative analysis of longitudinal gene expression changes.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
10 09 2022
10 09 2022
Historique:
received:
15
04
2021
revised:
17
01
2022
accepted:
18
01
2022
pubmed:
15
2
2022
medline:
20
9
2022
entrez:
14
2
2022
Statut:
ppublish
Résumé
Type 2 diabetes is a complex, systemic disease affected by both genetic and environmental factors. Previous research has identified genetic variants associated with type 2 diabetes risk; however, gene regulatory changes underlying progression to metabolic dysfunction are still largely unknown. We investigated RNA expression changes that occur during diabetes progression using a two-stage approach. In our discovery stage, we compared changes in gene expression using two longitudinally collected blood samples from subjects whose fasting blood glucose transitioned to a level consistent with type 2 diabetes diagnosis between the time points against those who did not with a novel analytical network approach. Our network methodology identified 17 networks, one of which was significantly associated with transition status. This 822-gene network harbors many genes novel to the type 2 diabetes literature but is also significantly enriched for genes previously associated with type 2 diabetes. In the validation stage, we queried associations of genetically determined expression with diabetes-related traits in a large biobank with linked electronic health records. We observed a significant enrichment of genes in our identified network whose genetically determined expression is associated with type 2 diabetes and other metabolic traits and validated 31 genes that are not near previously reported type 2 diabetes loci. Finally, we provide additional functional support, which suggests that the genes in this network are regulated by enhancers that operate in human pancreatic islet cells. We present an innovative and systematic approach that identified and validated key gene expression changes associated with type 2 diabetes transition status and demonstrated their translational relevance in a large clinical resource.
Identifiants
pubmed: 35157052
pii: 6528271
doi: 10.1093/hmg/ddac039
pmc: PMC9476627
doi:
Substances chimiques
Blood Glucose
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3191-3205Subventions
Organisme : NHGRI NIH HHS
ID : R01 HG011138
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM133169
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142302
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002243
Pays : United States
Organisme : NHGRI NIH HHS
ID : R35 HG010718
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000371
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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