Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study.

Tess V Clendenen,Eva Lundin,Wenzhen Ge,Karen L Koenig,Tomas Axelsson,Roy E Shore,Anne Andersson,Yelena Afanasyeva,Göran Hallmans,Malin Sund,Per Lenner,Tomas Kirchhoff,Yu Chen,Mengling Liu,Anne Zeleniuch-Jacquotte,Alan A Arslan

doi:10.1371/journal.pone.0140478

Abstract

Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.

Highlights

In vitro and in vivo studies suggest that vitamin D may have a protective effect against breast cancer due to its role in regulating cell growth and apoptosis [1]
The proportion of nulliparous women was higher in cases than controls (8% vs. 6%, p = 0.07), and among parous women, cases tended to have been older at first full term pregnancy than controls
We did not observe differences in the Single nucleotide polymorphisms (SNPs)-breast cancer risk associations according to menopausal status of the study subjects or estrogen receptor status of the breast tumors. In this nested case-control study among Swedish women, we confirmed the association of SNPs in CYP2R1, DHCR7, and GC/VDBP with 25(OH)D concentrations that were reported by genome wide association studies (GWAS) [26, 27]

Summary

Introduction

In vitro and in vivo studies suggest that vitamin D may have a protective effect against breast cancer due to its role in regulating cell growth and apoptosis [1]. Single nucleotide polymorphisms (SNPs) in genes encoding proteins that act downstream of 25(OH)D production, including proteins related to vitamin D transport (e.g., vitamin D binding protein, GC/VDBP), metabolism (e.g., 24-hydroxylase, CYP24A1), and signaling (e.g., vitamin D receptor, VDR, and retinoid X receptor alpha, RXRA) may affect the inter-individual biological effects of vitamin D and influence risk (Fig 1, [7,8,9,10,11,12,13]). We genotyped the candidate SNPs in gene regions that were related to circulating 25(OH)D concentrations in genome wide association studies (GWAS) and/or other epidemiological studies (i.e., a 25-hydroxylase [CYP2R1], GC/VDBP, and 7-dehydrocholesterol reductase [DHCR7] [26,27,28,29,30,31]). We evaluated whether the association between these genetic polymorphisms and breast cancer risk varied according to the menopausal status of the subjects or the estrogen receptor status of the breast tumors

Objectives

Methods

Results

Discussion

Conclusion