{"doi":"10.1016/j.ekir.2025.09.053","title":"Exome-Wide Analysis Identifies a Rare EXD3 Missense Variant Associated With Diabetic Kidney Disease","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.","journal":"Kidney International Reports","year":2025,"id":535142,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.897,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":5013,"name":"Joanne B. 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