Abstract PO-143: Differences in vitamin D genomic and epigenomic responses in colonic organoids from African- and European-Americans

Abstract

Abstract 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)<5% were found. Gene set enrichment included the KEGG pathway “colorectal cancer” (FDR<5%) with differentially responsive genes such as APC and MYC. eQTL mapping showed 131 1,25vitD-only and 21 control-only significant variants (FDR<5%). For inter-ethnic 1,25vitD responses, top genes included MORC3, MAP4K3, AMACR, KYNU, PIK3CA and POLB. Results for POLB, a base-excision repair polymerase, were particularly interesting given significant inter-ethnic differences in genomic and epigenomic responses to 1,25vitD likely due to a genetic mechanism. Specifically, organoids from AA showed significantly higher POLB expression with 1,25vitD. In the region, a POLB eQTL, rs2272733, showed large allele frequency differences for the ancestral T allele (80% in Africa; 14% in Europe). This eQTL is located in a POLB enhancer region, and there is a vitamin D-responsive ATAC peak ~10kb 5' to this SNP that is only present in T/T genotypes. Conclusion: Application of organoids from diverse populations enables genome-wide assessment of population differences in host-environment interactions related to CRC. In this study, overall 1,25vitD responses were robust and found pathways relevant to CRC. eQTL mapping further established a genetic basis for 1,25vitD colonic responses. We found a number of genes that showed differences in 1,25vitD transcriptional response between AA and EA with a particularly promising CRC-relevant candidate gene, POLB. These results provide new insights into differences in host-environment interactions between populations that could underlie cancer disparities. 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.