2703-LB: A Circulating microRNA Signature for Familial Risk of Type 2 Diabetes and Renal Failure

Introduction and Objective: Circulating microRNAs (miRNAs) regulate metabolic and inflammatory pathways and may reflect genetic risk of type 2 diabetes (T2D) and renal failure (RF), captured through family history. Whether circulating microRNAs capture familial risk better than clinical characteristics is currently unknown.Methods: This cross-sectional design assessed a discovery subset (n=81) from a historical 2×2 factorial cohort (N=288) of unaffected Māori and Pasifika first-degree relatives with T2D and/or RF. Circulating miRNA abundance was measured using TaqMan PCR on the OpenArray platform. In the discovery subset, miRNAs with detectable signal (fold-over-detection, FoD>1) in ≥20% of participants were retained for analyses. Missing miRNA values were imputed using the median within the T2D/RF group. Log₂-transformed miRNA abundance was analyzed using linear regression models adjusted for age, sex, ethnicity, and mean arterial pressure (primary model), with additional adjustment for C-reactive protein (CRP) as sensitivity analysis. Multiple testing was controlled using the Benjamini-Hochberg false discovery rate (FDR q<0.05).Results: Of 754 assayed miRNAs, 111 met the detectability threshold with 17-99 miRNAs detected per individual. In models evaluating T2D, microRNAs miR-215, miR-1274A, miR-145, miR-320, miR-194, and miR-648 showed significantly lower abundance (2^-18 to <0.5-fold, q<0.05, all). The strongest signals came from the T2D×RF familial risk interaction, with miR-648 demonstrating the largest effect (~2¹⁴ to 2²⁸-fold, q<0.001). Positive interaction effects were also observed for miR-1274B, miR-215, miR-99b, miR-122, and miR-145 (2⁴ to <2¹²-fold, q<0.05, all). Principal component analysis and t-distributed stochastic neighbor embedding suggested that circulating miRNA profiles better separated familial risk groups than clinical characteristics.Conclusion: Circulating miRNA profiles differed with familial risk of T2D and RF, suggesting shared familial pathways to diabetic kidney disease risk.

K. Perera: None. M.V. Joglekar: None. H.P. Hardikar: None. R. Hayward: None. J. Baker: None. G.B. Sundborn: None. A.A. Hardikar: None. D. Simmons: Speaker’s Bureau; Ended; Novo Nordisk. Other – Educational grant; Ended; Abbott Diabetes. Research Support; Current; Novo Nordisk. Consultant; Ended; Dexcom, Inc.



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