Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations

• Main Authors: 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 Trichopoulou, Periklis 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
• Format: Article
• Language: English
• Published: MDPI AG 2019-08-01
• Series: Nutrients
• Subjects: single nucleotide polymorphism (SNP); vitamin D; colorectal neoplasms; incidence
• Online Access: https://www.mdpi.com/2072-6643/11/8/1954

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 <i>VDR</i>, <i>GC</i>, and <i>CYP27B1</i> 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 (<i>LRP2, CUBN, NCOA7</i>, and <i>HDAC9</i>). 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 (<i>P</i> ≤ 0.001), with most statistically significant genes being <i>SMAD7 (P_BH</i> = 0.008) and <i>SMAD3 (P_BH</i> = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (<i>P</i> = 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 <i>P</i> = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.