Back to Search
Start Over
Tissue-Specific Alteration of Metabolic Pathways Influences Glycemic Regulation
- Source :
- SSRN Electronic Journal.
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- SummaryMetabolic dysregulation in multiple tissues alters glucose homeostasis and influences risk for type 2 diabetes (T2D). To identify pathways and tissues influencing T2D-relevant glycemic traits (fasting glucose [FG], fasting insulin [FI], two-hour glucose [2hGlu] and glycated hemoglobin [HbA1c]), we investigated associations of exome-array variants in up to 144,060 individuals without diabetes of multiple ancestries. Single-variant analyses identified novel associations at 21 coding variants in 18 novel loci, whilst gene-based tests revealed signals at two genes, TF (HbA1c) and G6PC (FG, FI). Pathway and tissue enrichment analyses of trait-associated transcripts confirmed the importance of liver and kidney for FI and pancreatic islets for FG regulation, implicated adipose tissue in FI and the gut in 2hGlu, and suggested a role for the non-endocrine pancreas in glucose homeostasis. Functional studies demonstrated that a novel FG/FI association at the liver-enriched G6PC transcript was driven by multiple rare loss-of-function variants. The FG/HbA1c-associated, islet-specific G6PC2 transcript also contained multiple rare functional variants, including two alleles within the same codon with divergent effects on glucose levels. Our findings highlight the value of integrating genomic and functional data to maximize biological inference.Highlights23 novel coding variant associations (single-point and gene-based) for glycemic traits51 effector transcripts highlighted different pathway/tissue signatures for each traitThe exocrine pancreas and gut influence fasting and 2h glucose, respectivelyMultiple variants in liver-enriched G6PC and islet-specific G6PC2 influence glycemia
- Subjects :
- medicine.medical_specialty
G6PC2
pathways
Adipose tissue
Type 2 diabetes
Biology
effector transcript
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Diabetes mellitus
Internal medicine
0502 economics and business
medicine
Glucose homeostasis
genetics
050207 economics
030304 developmental biology
Glycemic
0303 health sciences
050208 finance
Pancreatic islets
05 social sciences
tissue
Genomics
medicine.disease
Endocrinology
medicine.anatomical_structure
chemistry
glycemic traits
Glycated hemoglobin
type 2 diabetes
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15565068
- Database :
- OpenAIRE
- Journal :
- SSRN Electronic Journal
- Accession number :
- edsair.doi.dedup.....785079dbcb50e1abe846740e443e2f2a