Vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western European populations.
File(s)nutrients-11-01954-v2.pdf (756.1 KB)
Published version
Author(s)
Type
Journal Article
Abstract
Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β (TGFβ) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (PBH = 0.008) and SMAD3 (PBH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.
Date Issued
2019-08-20
Date Acceptance
2019-08-12
Citation
Nutrients, 2019, 11 (8), pp.1-24
ISSN
2072-6643
Publisher
MDPI AG
Start Page
1
End Page
24
Journal / Book Title
Nutrients
Volume
11
Issue
8
Copyright Statement
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31434255
PII: nu11081954
Subjects
colorectal neoplasms
incidence
single nucleotide polymorphism (SNP)
vitamin D
Publication Status
Published
Coverage Spatial
Switzerland
OA Location
https://www.mdpi.com/2072-6643/11/8/1954
Date Publish Online
2019-08-20