Introduction and Objective: Accurate control population-based thresholds for Islet autoantibodies positivity are essential to diagnosed and predict type 1 diabetes (T1D). Most positivity thresholds come from European populations, and it remains unclear whether these thresholds differ across ancestries within the same country. Methods: We analyzed GADA, IA-2A and ZnT8A in 1543 diabetes-free adults (595 -European, 474 - African, 474 - Admixed American) from the Geisinger MyCode cohort. Autoantibodies were measured using RSR ELISA assays at the Exeter Biochemistry Laboratory, UK. We calculated 99th percentile cut-offs for each autoantibody by ancestry using bootstrap sampling (1000x). We assessed differences in 99th centile threshold across ancestries with quantile regression. We also evaluated the effects of age, sex and T1D genetic risk score (T1DGRS) on antibody titers using multivariable regression. Results: The median participant age was 33.2 years (IQR 27.5), and 69.5% were female. IA-2A and ZnT8A 99th thresholds 95% CI were similar across three ancestries (p=0.63). While the point estimate of 99th-percentile GADA thresholds was variable across ancestry with wide confidence intervals (EUR 7.80 4-1581, AFR 51.8 4-970, AMR 36.3 4-914), these differences did not approach statistical significance (p=0.99). Age, sex, ancestry, and T1D GRS were not associated with GADA or IA-2A titers (P 0.1). In contrast, ZnT8A titer declined modestly with age (β = -0.002, p 0.0001) and male sex (β = -0.068, p0.005), but not with ancestry or T1DGRS. Conclusion: Islet autoantibody positivity thresholds are consistent across ancestries within a country supporting a use of single multi-ancestry-derived cut-off for routine clinical use. The previously observed differences in antibody thresholds across countries likely stem from environmental rather than ancestral factors. Disclosure J. Li: None. A. Golden: None. R. Stahl: None. J.S. Haley: None. A. Jones: None. R.A. Oram: Other - Research support, The University of Exeter has a licensing and royalty agreement for a 10 SNP T1D GRS with Randox; Current; Randox. Other - Advisory Panel, Consulting, Invited talks; Current; Sanofi. Other - invited talk, internal teaching talk on genetics; Ended; Novo Nordisk. D. Carey: None. U. Mirshahi: None. K. Patel: None. Funding Breakthrough T1D (3-SRA-2022-1241-S-B)
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