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E-Poster Submission Deadline
Please prepare and upload your E-Poster no later than March 14, 2026 11.59PM CET. After this date, you will no longer be able to prepare and upload your E-poster and it will not be displayed and accessible on the congress website.
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Abstract titles should be brief and reflect the content of the abstract.
Type 2 diabetic nephropathy (T2DN) disproportionately affects individuals of African ancestry, who face a 3–4 times higher risk of T2D-end-stage renal disease (ESRD) compared to those of European ancestry. Previous studies identified ELMO1 as a candidate gene for protection in Black/African Americans (B/AA), yet lacked functional validation or cross-ancestry replication. We investigated genetic associations at the ELMO1 locus, fine-mapped candidate variants, assessed enhancer function, and evaluated ancestry-specific effects.
We analyzed variants in ELMO1, DOCK2, and RAC1 among 34,966 participants from the All of Us Research Program, stratified by genetically inferred ancestry into four groups: African ancestry (N=7,572), European ancestry (N=16,545), East Asian ancestry (N=727), and admixed ancestry (no single ancestry >50%; N=10,122). T2DN and T2D-ESRD cases (N=6,654) were defined using KDIGO criteria and compared to T2D controls without complications (n = 20,900). We tested single-variant associations using Firth logistic regression, adjusting for age at T2D diagnosis, sex, BMI, HbA1c, systolic blood pressure, and continuous genetic ancestry proportion. Linkage disequilibrium (LD)-aware gene-level correction using the Li-Ji Meff method, with Bonferroni-adjusted significance thresholds, was applied. We further conducted Sum of Single Effects (SuSiE) fine-mapping, functional annotation, and formal heterogeneity testing across ancestries.
In B/AAs (1,562 T2DN cases, 4,741 controls), three ELMO1 intronic variants achieved gene-level significance (P<0.038): rs140372714 (OR=0.79; P=0.034), rs10216057 (P=0.035), and rs7784438 (P=0.037). Fine-mapping identified rs140372714, a 4-bp deletion, as the lead variant (PIP=0.136), disrupting experimentally validated IRF1 and SOX transcription factor binding sites within an enhancer element. Chromatin states showed quiescent baseline activity in healthy kidneys, consistent with context-dependent activation under diabetic inflammatory conditions. No variants associated with HbA1c (all P>0.72), confirming kidney-specific rather than systemic metabolic effects. Interestingly, ancestry-specific heterogeneity was observed (Q=10.27; I²=71%; P=0.016). The protective deletion is the minor allele in African ancestry (MAF=39.5%), but the major allele in other populations (MAF>75%), where it shows opposite effects.
ELMO1 is a validated, ancestry-specific, kidney-protective locus for T2DN in those of African descent, supported by both statistical and functional evidence. The allele frequency reversal across ancestries highlights how population-specific evolutionary histories shape disease risk and emphasizes the need for genetically diverse cohorts and ancestry-aware analysis.
