Vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western european populations

Veronika Fedirko*, Hannah B. Mandle, Wanzhe Zhu, David J. Hughes, Afshan Siddiq, Pietro Ferrari, Isabelle Romieu, Elio Riboli, Bas Bueno-de-Mesquita, Fränzel J.B. Van Duijnhoven, Peter D. Siersema, Anne Tjønneland, Anja Olsen, Vittorio Perduca, Franck Carbonnel, Marie Christine Boutron-Ruault, Tilman Kühn, Theron Johnson, Aleksandrova Krasimira, Antonia TrichopoulouPeriklis Makrythanasis, Dimitris Thanos, Salvatore Panico, Vittorio Krogh, Carlotta Sacerdote, Guri Skeie, Elisabete Weiderpass, Sandra Colorado-Yohar, Núria Sala, Aurelio Barricarte, Maria Jose Sanchez, Ramón Quirós, Pilar Amiano, Björn Gylling, Sophia Harlid, Aurora Perez-Cornago, Alicia K. Heath, Konstantinos K. Tsilidis, Dagfinn Aune, Heinz Freisling, Neil Murphy, Marc J. Gunter, Mazda Jenab

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Article number1954
JournalNutrients
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 2019

Keywords

  • Colorectal neoplasms
  • Incidence
  • Single nucleotide polymorphism (SNP)
  • Vitamin D

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    Fedirko, V., Mandle, H. B., Zhu, W., Hughes, D. J., Siddiq, A., Ferrari, P., ... Jenab, M. (2019). Vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western european populations. Nutrients, 11(8), [1954]. https://doi.org/10.3390/nu11081954