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

TL;DR

This study shows how active vitamin D affects colon cells differently in people of African and European ancestry, identifying a genetic variant that influences DNA repair and cancer risk.

Contribution

The study identifies an ancestry-related regulatory variant of POLB that explains differences in vitamin D responses in colon cells.

Findings

1,25D treatment alters transcriptional and chromatin accessibility in colonic organoids with ancestry-associated differences.

An insertion-deletion variant explains ancestry-related differences in 1,25D regulation of POLB, a DNA repair enzyme linked to colorectal cancer.

The POLB variant shows signals of positive natural selection, suggesting evolutionary relevance to DNA repair and cancer prevention.

Abstract

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 across individuals of diverse ancestries. 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 variants on treatment responses. Integration of genomic profiling with genetic mapping found an insertion-deletion variant that explains ancestry-associated differences in 1,25D regulation of POLB, an oxidative DNA repair enzyme involved in colorectal carcinogenesis, which also showed signals of positive natural selection. These findings highlight the importance of including diverse individuals in functional genomics studies to identify potential drivers of population-level differences relevant for clinical outcomes, and to uncover functional mechanisms that may be obscured by ancestry variation.

In our study, we aimed to understand how active vitamin D affects colon cells from people with African and European backgrounds. Colon health is important for everyone, especially since conditions like colon cancer can be influenced by vitamin D responses. Leveraging an experimental approach in which we treated colonic organoids, also known as “mini-guts”, from people of different backgrounds with active vitamin D, we found that genes and cell structures respond differently to vitamin D, some of which depend on a person’s ancestry. We discovered that vitamin D changes the activity of many genes and some of these changes are different depending on a person’s ancestry.

We found one specific genetic difference that helps explain why an important gene called polymerase beta, or POLB, which is involved in repairing DNA and prevention of colon cancer, responds more strongly to vitamin D in certain populations. Including people with different backgrounds in genetic research is critical to better understand how treatments like vitamin D might work differently for heterogeneous groups and could improve health care for everyone.

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