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Vitamin D receptor genotype,
vitamin D3 supplementation,
and risk of colorectal adenomas
By Sonia S. Kupfer,
MD,
Marc Bissonnette,
MD,
Yan-Chun LI,
PhD
V
itamin D regulates a
plethora of biological
processes mediated by
the vitamin D receptor (VDR)
and is postulated to inhibit colon
cancer development.
1–5
However,
a recent study of vitamin D
and calcium intervention by
Dr Baron’s group failed to
support this hypothesis, with no
differences in polyp recurrence
noted in individuals randomised
to vitamin D and/or calcium
compared with those randomised
to placebo.
6
Caveats were noted
with the study, including the
dose of vitamin D.
7
Growing evidence supports the
hypothesis that single nucleo-
tide polymorphisms (SNPs) can
modulate gene expression and
colon cancer risk.
8,9
To further
explore potential confounders for
the negative results, the authors
examined 41 candidate SNPs in
genes associated with vitamin D
and calcium signalling. The in-
vestigators identified two SNPs
in the 3’ untranslated region
(UTR) of VDR (rs7968585 and
rs731236) in linkage disequilibri-
um that varied significantly with
effects of vitamin D3 supplemen-
tation on advanced adenoma oc-
currence. For rs7968585, among
individuals with the AA genotype
(26%), vitamin D3 supplementa-
tion reduced advanced polyp risk
by 64%, whereas in those with
1 or 2 G alleles (74%), vitamin
D3 supplementation increased
advanced polyp risk by 41%.
Therefore, the authors specu-
lated that effects of vitamin D
supplementation are dependent
on VDR genotype. The effects
of the SNPs were not related to
changes in serum vitamin D lev-
els, suggesting that these SNPs
modulate risk independent of
serum vitamin D levels.
More work is obviously needed
to determine the mechanisms of
these genotypic effects. SNPs in
the 3’ UTR could, for example,
alter mRNA splicing or microR-
NA binding, modulating mRNA
stability or translational effi-
ciency. This study has identified
potentially important associa-
tions but lacks the ability to make
causal connections, emphasising
the challenges of determining
underlying mechanisms when
studying interventions such as vi-
tamin D in colon cancer preven-
tion. Crispr-Cas9 genetic tools
that are capable of making alter-
ations to single DNA bases could
be used to dissect molecular al-
terations regulated by SNPs.
10,11
When applied to model systems
or genetically engineered mice,
such studies could determine
whether targeted SNPs regulate
VDR gene expression and vita-
min D effects on colon cancer
development. Such insights from
cell and mouse models could
strengthen the rationale to un-
dertake chemoprevention studies
in populations expressing SNPs
predicted to respond to anti-can-
cer effects of vitamin D or other
agents. If such investigations are
successful, we would be much
closer to practicing personalised
medicine.
References
1. Carlberg C.
Front Physiol
2014;5:167.
2. Lee JE, Li H, Chan AT, et al.
Cancer
Prev Res (Phila)
2011;4:735-743.
3. Lamprecht SA, Lipkin M.
Nat Rev
Cancer
2003;3:601-614
4. Dougherty U, Mustafi R,
Sadiq A, et al.
Clin Cancer Res
2014;20:5848-5859.
5. Zheng W, Wong KE, Zhang Z, et al.
Int J Cancer
2012;130: 10-19.
6. Baron JA, Barry EL, Mott LA, et al.
N Engl J Med
2015;373:1519-1530.
7. Kupfer SS, Li YC, Bissonnette.
Nutr
Cancer
2017;69(1):167.
8. Kang EY, Martin L, Mangul
S, et al.
Genetics
DOI:1534/
genetics.115.177246.
9. Kupfer SS, Torres JB, Hooker
S, et al.
Carcinogenesis
2009;30:1353-1357.
10. Courtney DG, Moore JE,
Atkinson SD, et al.
Gene Ther
2016;23(1):108-112.
11. Beaudoin M, Gupta RM, Won HH,
et al.
Arterioscler Thromb Vasc Biol
2015;35:1472-1479.
Dr Kupfer is Assistant Professor in
the Section of Gastroenterology
and Director of the
Gastrointestinal Cancer Risk and
Prevention clinic at the University
of Chicago; Dr Bissonnette and
Dr Li are Associate Professor
of the Department of Medicine
– Section of Gastroenterology,
Cancer Research Centre and
on the Committee on Molecular
Metabolism and Nutrition,
The University of Chicago.
Vitamin D receptor genotype, vitamin D3 supplementation, and risk of
colorectal adenomas: a randomized clinical trial
JAMA Oncol
2016 Dec 15;[EPub Ahead of Print], EL Barry, JL Peacock, JR Rees, et al.
Take-home message
•
In this randomised, double-blind, multisite study, 41 single-nucleotide polymorphisms (SNPs) in vitamin D
and calcium pathway genes were analysed in patients with colorectal adenomas. Based on data from 1702
non-Hispanic whites, two SNPs (rs7968585 and rs731236) in vitamin D receptors were significantly linked
to the impact of vitamin D3 supplementation. Vitamin D3 supplementation decreased risk for advanced
adenomas by 64% among individuals with the AA genotype (26%) at the rs7968585 SNP. Risk increased
by 41% in individuals with one or two G alleles (74%). The benefits of supplementation with calcium were
not significantly linked to genotype.
•
For the prevention of advanced colorectal adenomas, the benefits of vitamin D3 supplementation may
vary based on the vitamin D receptor genotype.
Such insights from cell and mouse models
could strengthen the rationale to undertake
chemoprevention studies in populations
expressing SNPs predicted to respond to anti-
cancer effects of vitamin D or other agents.
If such investigations are successful, we would
be much closer to practicing personalised
medicine.
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