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Background: African Americans have the highest burden of colorectal cancer (CRC) in the US. Active 1,25(OH)2vitamin D (1,25vitD) protects from CRC, though the role of population differences in 1,25vitD responses to CRC disparities is unknown. To study inter-ethnic host-environment interactions in the colon, we have established human-derived colonic organoids from diverse populations. We used this approach to study differences in transcriptional and chromatin accessibility responses to 1,25vitD between Americans of African (AA) and European (EA) ancestry. Methods: Colonic organoids from 60 subjects (30 AA and 30 EA) were established. After passaging, organoids were differentiated for 24h and then treated with 100nM 1,25vitD or ethanol (vehicle control). Chromatin accessibility and gene expression were assessed at 4 and 6 hours by RNA-seq and ATAC-seq, respectively. Inter-ethnic responses were assessed using dream (Hoffman et al, 2020). Genotyping was performed using the Infinium OmniExpress-24, and ancestry was estimated using imputed genotypes. Expression quantitative trait loci (eQTL) mapping was performed using BRIdGE (Maranville et al, 2011). Results: Organoid lines from 54 subjects (28 AA and 26 EA) were included after removing 5 with inconsistent ancestry. For overall 1,25vitD response, 7816 differentially expressed protein-coding genes at a false discovery rate (FDR) Citation Format: Sonia Kupfer, David Witonsky, Jinchao Li, Margaret Bielski, Kristi Lawrence. Differences in vitamin D genomic and epigenomic responses in colonic organoids from African- and European-Americans [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-143.