Genomic profiling of active vitamin D colonic responses in African- and European-Americans identifies an ancestry-related regulatory variant of POLB

We measured genomic responses to active vitamin D, 1a,25-dihydroxyvitamin D (1,25D), in colonic organoids from individuals of African and European ancestry. Given protective effects of 1,25D for gastrointestinal conditions such as colorectal cancer, organoid cultures enabled evaluation of condition-specific responses in relevant target tissue. We found significant alterations in transcriptional and chromatin accessibility responses to 1,25D treatment, including some with ancestry-associated differences, and also elucidated the role of cis-genetic variance on treatment responses. Integration of genomic profiling with genetic mapping found an indel that explains ancestry-associated differences in the regulation of POLB response to 1,25D which showed signals of positive natural selection. Overall design: Human colonic organoids derived from indivdiuals of African ancestry (AA) and European ancestry (EA) were cultured, differentiated, and treated with either 100nm/L 1a,25-dihydroxyvitamin D (1,25D) or vehicle control (0.1% ethanol). RNA and DNA was extracted for RNA-seq and ATAC-seq. Treatment time was 4 hours for ATAC-seq and 6 hours for RNA-seq. After applying QC filters, paired treatment and control samples were available for 53 individuals (26 AA/27 EA) for RNA-seq analysis and 25 individuals (10 AA/15 EA) for ATAC-seq analysis. Differentially responsive genes and differential chromatin accessibility were analyzed in the set of all samples as well as by population. eQTL and aQTL mapping was also performed to identify genetic variants associated with condition-specific responses and chromatin accessibility.