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Exome-Wide Analysis Identifies a Rare EXD3 Missense Variant Associated With Diabetic Kidney Disease
Niina Sandholm1,2,3, Joanne B Cole4,5,6,7,8, Viji Nair9
1Folkhälsan Research Center, Helsinki, Finland.
Kidney International Reports
|January 16, 2026
Summary
A rare EXD3 gene variant significantly increases diabetic kidney disease risk in type 1 diabetes patients. Functional studies indicate EXD3 plays a role in podocyte integrity, suggesting new therapeutic targets for DKD.
Area of Science:
- Genetics
- Nephrology
- Endocrinology
Background:
- Diabetic kidney disease (DKD) is a serious diabetes complication with a significant genetic component.
- Genome-wide association studies (GWAS) have identified common variants, but low-frequency and rare coding variants in DKD pathogenesis are underexplored.
Purpose of the Study:
- To investigate the role of low-frequency and rare coding variants in diabetic kidney disease (DKD) susceptibility.
- To identify novel genetic factors contributing to DKD in individuals with type 1 diabetes (T1D).
Main Methods:
- Exome-wide meta-analysis of up to 10,312 individuals with T1D, analyzing nonsynonymous variants.
- Gene-level analyses for low-frequency and rare variants, with replication in independent cohorts (T1D and type 2 diabetes [T2D]).
- Functional assessment of gene expression in cultured human podocytes.
Main Results:
- A novel rare missense variant in the EXD3 gene (rs200080727) was strongly associated with DKD risk (OR = 8.7, P = 4.5 × 10^-9).
- EXD3 was downregulated in DKD kidney tissues, and its knockdown in podocytes reduced nephrin expression, indicating a functional role.
- Gene-level analyses identified 7 DKD-associated genes, including MUC5B, with replication evidence.
Conclusions:
- A rare EXD3 variant is a significant risk factor for DKD in T1D.
- EXD3 is implicated in podocyte integrity and DKD pathogenesis, warranting further investigation into its molecular mechanisms.
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