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, 1α,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.