| Title: | Exome-Wide Analysis Identifies a Rare EXD3 Missense Variant Associated With Diabetic Kidney Disease |
| Journal: | Kidney International Reports |
| Published: | 1 Jan 2026 |
| DOI: | https://doi.org/10.1016/j.ekir.2025.09.053 |
| URL: | https://www.kireports.org/article/S2468-0249(25)00649-7/pdf |
Publication 16928
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Abstract
Introduction Diabetic kidney disease (DKD) is a major complication of diabetes, with genetic factors contributing to its progression. Although genome-wide association studies (GWAS) have identified common variants, the role of low-frequency and rare coding variants remains underexplored. Methods We performed exome-wide meta-analysis of up to 10,312 individuals with type 1 diabetes (T1D) genotyped using genome arrays with focused exome content. We included 10 DKD definitions based on albuminuria, estimated glomerular filtration rate (eGFR), or both. We analyzed nonsynonymous variants individually and used gene-level analyses for low-frequency (minor allele frequency [MAF] < 5%) and rare (< 1%) variants. Replication was performed in 10,066 participants with T1D and in UK Biobank participants with type 2 diabetes (T2D). Gene expression was assessed in cultured human podocytes. Results In addition to the known COL4A3 variant, a novel rare missense variant in EXD3 (p.Asp555Asn, rs200080727, minor allele frequency [MAF] = 0.4%) was associated with DKD (odds ratio [OR] = 8.7, P = 4.5 × 10-9). The variant was predicted to be deleterious and EXD3 was downregulated in DKD in kidney expression datasets. EXD3 knock-down in a cultured human podocyte cell line reduced nephrin gene expression, suggesting a functional role in podocyte biology. Gene-level analyses identified 7 DKD-associated genes (P < 3.4 × 10−6), including MUC5B, which harbored multiple low-frequency missense variants and with evidence of replication. Replication in UK Biobank supported the association of EXD3 rs200080727 with albuminuria (P = 0.014). Conclusion This study identified a rare EXD3 variant with a strong effect on DKD risk in T1D. Functional data support a role for EXD3 in podocyte integrity and DKD pathogenesis. However, further functional investigations are necessary to understand the underlying molecular mechanisms.</p>
74 Authors
- Niina Sandholm
- Joanne B. Cole
- Viji Nair
- Eoin Brennan
- Elena Giardini
- Jani K. Haukka
- Eunji Ha
- Anna Syreeni
- Emma H. Dahlström
- Rany M. Salem
- Damian Fermin
- Josep Mercader
- Laura Smyth
- Claire Hill
- Josyf Mychaleckyj
- Stuart McGurnaghan
- Rachel G. Miller
- Tina Costacou
- Barbara E.K. Klein
- Janet Snell-Bergeon
- Andrew D. Paterson
- Rasa Verkauskiene
- Jelizaveta Sokolovska
- Nicolae Mircea Panduru
- Gianpaolo Zerbini
- Kerstin Brismar
- Andrzej S. Krolewski
- Valma Harjutsalo
- Peter Rossing
- Samy Hadjadj
- Gareth McKay
- Amy Jayne McKnight
- Alexander P. Maxwell
- Katalin Susztak
- Catherine Godson
- Matthias Kretzler
- Joel N. Hirschhorn
- Jose C. Florez
- Per-Henrik Groop
- GENIE Consortium
- Joel N. Hirschhorn
- Jose C. Florez
- Xiaoqi Luo
- Emma H. Dahlström
- Anna Syreeni
- Erkka Valo
- Valma Harjutsalo
- Per-Henrik Groop
- Niina Sandholm
- Laura J. Smyth
- Katie Kerr
- Jill Kilner
- Yogesh Gupta
- Claire Hill
- Christopher Wooster
- Kerry Anderson
- Amy Jayne McKnight
- Alexander P. Maxwell
- Ciarán Kennedy
- Elena Giardini
- Ross Doyle
- Eoin Brennan
- Darrell Andrews
- Denise Sadlier
- Finian Martin
- Catherine Godson
- Viji Nair
- Damian Fermin
- Lalita Subramanian
- Matthias Kretzler
- Hongbo Liu
- Katalin Susztak
- Rany M. Salem
- Joanne B. Cole
1 Application
| Application ID | Title |
|---|---|
| 27892 | Genetic studies of type 2 diabetes, related metabolic traits, and their complications |
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