Exome-Wide Analysis Identifies a Rare EXD3 Missense Variant Associated With Diabetic Kidney Disease
Bibliographic record
Abstract
Introduction Diabetic kidney disease (DKD) is a major complication of diabetes, with genetic factors contributing to its progression.While genome-wide association studies have identified common variants, the role of low-frequency and rare coding variants remains underexplored. MethodsWe 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 ten DKD definitions based on albuminuria, eGFR, or both.We analyzed non-synonymous variants individually, and using gene-level analyses for low-frequency (minor allele frequency <5%) and rare (<1%) variants.Replication was performed in 10,066 participants with T1D and in UK Biobank participants with type 2 diabetes.Gene expression was assessed in cultured human podocytes. ResultsIn addition to the known COL4A3 variant, a novel rare missense variant in EXD3 (p.Asp555Asn, rs200080727, MAF=0.4%) was associated with DKD (OR=8.7,p=4.510 -9 ).The variant was predicted to be deleterious and EXD3 was downregulated in DKD in kidney expression datasets.EXD3 knockdown in a cultured human podocyte cell line reduced nephrin gene expression, suggesting a functional role in podocyte biology.Gene-level analyses identified seven DKD-associated genes (p<3.410 -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). ConclusionThis 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.012 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".