Pathogenic monoallelic variants in GLIS3 increase type 2 diabetes risk and identify a subgroup of patients sensitive to sulfonylureas
Pooled resultResult — go to the resultOdds ratio 3.9 95% CI 1.4–12Authors' conclusion
Rare P/LP GLIS3 variants do contribute to type 2 diabetes risk. The variants located in the distal part of the protein could have a direct effect on its functional activity by impacting its transactivation domain, by homology with the mouse GLIS3 protein. Furthermore, rare P/LP GLIS3 variants seem to have a direct clinical effect on beta cell function, which could be improved by increasing insulin secretion via the use of sulfonylureas.
Study context
- Population
- Individuals from the RaDiO study; replication in the 52K study (43,125 individuals) and TOPMed study (44,083 individuals)RaDiO
- Participants
- 5,471 individuals
- Comparison
- Carriers of rare P/LP GLIS3 variants vs non-carriers
- Outcome
- Association between rare P/LP GLIS3 variants and T2D risk
Methodological detailstargeted resequencing, ACMG variant classification, luciferase functional assays, meta-analysis of RaDiO, 52K and TOPMed
- Targeted resequencing
- ACMG variant classification
- Luciferase functional assays
- Meta-analysis of RaDiO, 52K and TOPMed
Pooled result
As reported in the abstract
Odds ratio
3.9
95% CI 1.4–12
P = 3.0×10-3
Further pooled results
Meta-analysis (RaDiO, 52K, TOPMed): enrichment of P/LP GLIS3 variants in individuals with T2D
- OR
- 2.1 (95% CI 1.4, 2.9)
- P value
- P = 5.6×10-5
- 7 P/LP variants identified in both 52K and TOPMed
Clinical traits in carriers vs non-carriers with T2D
- Adiposity, age at T2D diagnosis and cholesterol similar between variant carriers and non-carriers with T2D
Sulfonylurea sensitivity in carriers with T2D
- All carriers with T2D were sensitive to oral sulfonylureas
Location of P/LP variants: last two exons vs remaining exons
- Enrichment in last two exons, OR
- OR>3.5
- P value
- P < 5×10-6
- 18 rare variants classified as P/LP
Original publication
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