TY - JOUR

T1 - Associations between common polymorphisms in CYP2R1 and GC, Vitamin D intake and risk of colorectal cancer in a prospective case-cohort study in Danes

AU - Kopp, Tine Iskov

AU - Vogel, Ulla

AU - Andersen, Vibeke

PY - 2020

Y1 - 2020

N2 - BACKGROUND: The association between vitamin D and incidence of colorectal cancer has been thoroughly investigated, but the results are conflicting. The objectives in this study were to investigate whether two functional polymorphisms in GC and CYP2R1, respectively, previously shown to predict vitamin D concentrations, were associated with risk of colorectal cancer; and further, to assess gene-environment interaction between the polymorphisms and intake of vitamin D through diet and supplementation in relation to risk of colorectal cancer.METHODS: A nested case-cohort study of 920 colorectal cancer cases and 1743 randomly selected participants from the Danish prospective "Diet, Cancer and Health" study was performed. Genotypes CYP2R1/rs10741657 and GC/rs4588 were determined by PCR-based KASP™ genotyping assay. Vitamin D intake from supplements and diet was assessed from a validated food frequency questionnaire. Incidence rate ratios were estimated by the Cox proportional hazards model, and interactions between polymorphisms in GC and CYP2R1 and vitamin D intake in relation to risk of colorectal cancer were assessed.RESULTS: Neither of the two polymorphisms was associated with risk of colorectal cancer per se. Heterozygote carriage of CYP2R1/rs10741657 and GC/rs4588, and carriage of two risk alleles (estimated by a genetic risk score) were weakly associated with 9-12% decreased risk of colorectal cancer per 3 μg intake of vitamin D per day (IRRCYP2R1/rs10741657 = 0.88, 95% CI: 0.79-0.97; IRRGC/rs4588 = 0.91, 95% CI: 0.82-1.01, IRRGRS2 = 0.90, 95% CI: 0.81-0.99).CONCLUSIONS: The results suggest that genetic variation in vitamin D metabolising genes may influence the association between vitamin D intake, through food and supplementation, and risk of colorectal cancer.CLINICAL TRIAL REGISTRY: NCT03370432. Registered 12 December 2017 (retrospectively registered).

AB - BACKGROUND: The association between vitamin D and incidence of colorectal cancer has been thoroughly investigated, but the results are conflicting. The objectives in this study were to investigate whether two functional polymorphisms in GC and CYP2R1, respectively, previously shown to predict vitamin D concentrations, were associated with risk of colorectal cancer; and further, to assess gene-environment interaction between the polymorphisms and intake of vitamin D through diet and supplementation in relation to risk of colorectal cancer.METHODS: A nested case-cohort study of 920 colorectal cancer cases and 1743 randomly selected participants from the Danish prospective "Diet, Cancer and Health" study was performed. Genotypes CYP2R1/rs10741657 and GC/rs4588 were determined by PCR-based KASP™ genotyping assay. Vitamin D intake from supplements and diet was assessed from a validated food frequency questionnaire. Incidence rate ratios were estimated by the Cox proportional hazards model, and interactions between polymorphisms in GC and CYP2R1 and vitamin D intake in relation to risk of colorectal cancer were assessed.RESULTS: Neither of the two polymorphisms was associated with risk of colorectal cancer per se. Heterozygote carriage of CYP2R1/rs10741657 and GC/rs4588, and carriage of two risk alleles (estimated by a genetic risk score) were weakly associated with 9-12% decreased risk of colorectal cancer per 3 μg intake of vitamin D per day (IRRCYP2R1/rs10741657 = 0.88, 95% CI: 0.79-0.97; IRRGC/rs4588 = 0.91, 95% CI: 0.82-1.01, IRRGRS2 = 0.90, 95% CI: 0.81-0.99).CONCLUSIONS: The results suggest that genetic variation in vitamin D metabolising genes may influence the association between vitamin D intake, through food and supplementation, and risk of colorectal cancer.CLINICAL TRIAL REGISTRY: NCT03370432. Registered 12 December 2017 (retrospectively registered).

KW - Cholestanetriol 26-Monooxygenase/genetics

KW - Colorectal Neoplasms/blood

KW - Cytochrome P450 Family 2/genetics

KW - Denmark

KW - Dietary Supplements

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Vitamin D/administration & dosage

KW - Vitamin D-Binding Protein/genetics

U2 - 10.1371/journal.pone.0228635

DO - 10.1371/journal.pone.0228635

M3 - Journal article

C2 - 32012190

VL - 15

SP - e0228635

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 2

ER -