A Gene Pathway Approach To Study The Biological Effects Of Vitamin D On Colorectal Tumourigenesis

Mazda JENAB, International Agency for Research on Cancer (IARC-WHO), France
FEDIRKO V. 2 , GUNTER M. 1, 3 , RIBOLI E. 3

1 Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
2 Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, USA
3 Faculty of Medicine, School of Public Health, Imperial College London, London, UK

Purpose:  Biological plausibility, extensive experimental evidence and strong supportive data from prospective observational studies point towards a protective effect of higher circulating vitamin D [25(OH)D] levels against colorectal cancer (CRC) development. However, it is unclear whether or to what extent this association is modified by variation in genes involved in 25(OH)D metabolism and signaling.
Methods: 939 tagging single nucleotide polymorphisms (SNPs) in the vitamin D pathway [including genes related to vitamin D metabolism, mineral homeostasis, and vitamin D receptor (VDR) genomic effects] were analyzed in 1,420 CRC cases and 1,420 matched controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) study using a custom Illumina Goldengate genotyping assay. Multivariable odds ratios and 95% confidence intervals were calculated using conditional logistic regression. The adaptive rank-truncated product (ARTP) method implemented in R-package PIGE was used for pathway analysis.
Results: 100 SNPs in 29 genes related to vitamin D metabolism (CYP24A1/CYP2R1/CYP3A4/GC, etc.), mineral homeostasis (CASR), and genomic effects (VDR/RXRA, etc.) were statistically significantly associated with CRC risk (raw P-values < 0.05), but lost significance after correction for multiple testing. Among controls, 34 SNPs [including 6 SNPs previously identified to be associated with 25(OH)D in GWAS] in 17 genes were statistically significantly associated with season-adjusted concentration of 25(OH)D (raw P-values < 0.05; all non-significant after multiple testing correction). Pathway analyses showed no statistically significant effects on CRC risk for either individual genes or genes grouped into distinct pathways. However, the data suggested that risk associations with genes in vitamin D metabolism pathways may depend on interactions with circulating 25(OH)D (P = 0.06).
Conclusions: The findings from this prospective nested case-control study suggest that common genetic variation in an array of genes related to vitamin D metabolism likely have little influence on the vitamin D-CRC risk association in Western Europeans.