Colonic transcriptional response to 1α,25(OH)2vitamin D3in African- and European-Americans.
Colorectal cancer (CRC) is a significant health burden especially among African Americans (AA). Epidemiological studies have correlated low serum vitamin D with CRC risk, and, while hypovitaminosis D is more common and more severe in AA, the mechanisms by which vitamin D modulates CRC risk and how these differ by race are not well understood. Active vitamin D (1α,25(OH)2D3) has chemoprotective effects primarily through transcriptional regulation of target genes in the colon. We hypothesized that transcriptional response to 1α,25(OH)2D3differs between AA and European Americans (EA) irrespective of serum vitamin D and that regulatory variants could impact transcriptional response. We treated ex vivo colon cultures from 34 healthy subjects (16 AA and 18 EA) with 0.1μM 1α,25(OH)2D3or vehicle control for 6h and performed genome-wide transcriptional profiling. We found 8 genes with significant differences in transcriptional response to 1α,25(OH)2D3between AA and EA with definitive replication of inter-ethnic differences for uridine phosphorylase 1 (UPP1) and zinc finger-SWIM containing 4 (ZSWIM4). We performed expression quantitative trait loci (eQTL) mapping and identified response cis-eQTLs for ZSWIM4 as well as for histone deacetylase 3 (HDAC3), the latter of which showed a trend toward significant inter-ethnic differences in transcriptional response. Allele frequency differences of eQTLs for ZSWIM4 and HDAC3 accounted for observed transcriptional differences between populations. Taken together, our results demonstrate that transcriptional response to 1α,25(OH)2D3differs between AA and EA independent of serum 25(OH)D levels. We provide evidence in support of a genetic regulatory mechanism underlying transcriptional differences between populations for ZSWIM4 and HDAC3. Further work is needed to elucidate how response eQTLs modify vitamin D response and whether genotype and/or transcriptional response correlate with chemopreventive effects. Relevant biomarkers, such as tissue-specific 1α,25(OH)2D3transcriptional response, could identify individuals likely to benefit from vitamin D for CRC prevention as well as elucidate basic mechanisms underlying CRC disparities.
University of Chicago, Department of Medicine, Section of Gastroenterology, Chicago, IL, United States.
Dereck
D
Alleyne
University of Chicago, Department of Human Genetics, Chicago, IL, United States.
David B
DB
Witonsky
University of Chicago, Department of Medicine, Section of Gastroenterology, Chicago, IL, United States.
Brandon
B
Mapes
University of Chicago, Department of Human Genetics, Chicago, IL, United States.
Shigeki
S
Nakagome
University of Chicago, Department of Medicine, Section of Gastroenterology, Chicago, IL, United States.
Meredith
M
Sommars
University of Chicago, Department of Medicine, Section of Gastroenterology, Chicago, IL, United States.
Ellie
E
Hong
University of Chicago, Department of Medicine, Section of Gastroenterology, Chicago, IL, United States.
Katy A
KA
Muckala
University of Chicago, Department of Human Genetics, Chicago, IL, United States.
Anna
A
Di Rienzo
University of Chicago, Department of Medicine, Section of Gastroenterology, Chicago, IL, United States. Electronic address: skupfer@medicine.bsd.uchicago.edu.
Sonia S
SS
Kupfer
D001741:Black or African American; D000483:Alleles; D001706:Biopsy; D044383:Black People; D002117:Calcitriol / Q000378:metabolism*; D015331:Cohort Studies; D003106:Colon / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D009924:Organ Culture Techniques; D040641:Quantitative Trait Loci; D014158:Transcription, Genetic; D014481:United States; D014543:Uridine Phosphorylase / Q000096:biosynthesis* / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism; D044465:White People
D004268:DNA-Binding Proteins; D014807:Vitamin D; C000620962:UPP1 protein, human; D014543:Uridine Phosphorylase; D002117:Calcitriol
Colorectal cancer; Expression quantitative trait loci; Gene transcription; Health disparities; Vitamin D