TY - JOUR

T1 - Vitamin D-related genes, blood vitamin D levels and colorectal cancer risk in western european populations

AU - Fedirko, Veronika

AU - Mandle, Hannah B.

AU - Zhu, Wanzhe

AU - Hughes, David J.

AU - Siddiq, Afshan

AU - Ferrari, Pietro

AU - Romieu, Isabelle

AU - Riboli, Elio

AU - Bueno-de-Mesquita, Bas

AU - Van Duijnhoven, Fränzel J.B.

AU - Siersema, Peter D.

AU - Tjønneland, Anne

AU - Olsen, Anja

AU - Perduca, Vittorio

AU - Carbonnel, Franck

AU - Boutron-Ruault, Marie Christine

AU - Kühn, Tilman

AU - Johnson, Theron

AU - Krasimira, Aleksandrova

AU - Trichopoulou, Antonia

AU - Makrythanasis, Periklis

AU - Thanos, Dimitris

AU - Panico, Salvatore

AU - Krogh, Vittorio

AU - Sacerdote, Carlotta

AU - Skeie, Guri

AU - Weiderpass, Elisabete

AU - Colorado-Yohar, Sandra

AU - Sala, Núria

AU - Barricarte, Aurelio

AU - Sanchez, Maria Jose

AU - Quirós, Ramón

AU - Amiano, Pilar

AU - Gylling, Björn

AU - Harlid, Sophia

AU - Perez-Cornago, Aurora

AU - Heath, Alicia K.

AU - Tsilidis, Konstantinos K.

AU - Aune, Dagfinn

AU - Freisling, Heinz

AU - Murphy, Neil

AU - Gunter, Marc J.

AU - Jenab, Mazda

N1 - Publisher Copyright: © 2019 by the authors.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Colorectal neoplasms

KW - Incidence

KW - Single nucleotide polymorphism (SNP)

KW - Vitamin D

U2 - 10.3390/nu11081954

DO - 10.3390/nu11081954

M3 - Journal article

C2 - 31434255

AN - SCOPUS:85071548952

VL - 11

JO - Nutrients

JF - Nutrients

SN - 2072-6643

IS - 8

M1 - 1954

ER -