Serum 25-hydroxyvitamin D, vitamin D receptor gene polymorphisms and haplotypes and risk of postmenopausal breast cancer in a large case-control study

B102

Introduction
 >In observational studies, vitamin D intake and serum concentrations of vitamin D metabolites have been associated with a decreased risk of developing breast cancer. Beside its role in maintenance of calcium homeostasis, its antiproliferative effects by influencing cell differentiation, cell growth and apoptosis, are well established. Vitamin D mainly exerts its antiproliferative effects by binding to the vitamin D receptor (VDR) and acting in complex as a transcriptional factor for a variety of genes including those involved in cell differentiation and cell growth. Various studies have assessed the association of different polymorphisms in the VDR and breast cancer risk with inconsistent results, however, only one study so far assessed the association in relation to plasma 25-hydroxyvitamin D [25(OH)D], a biomarker for vitamin D status in humans. We therefore examined the association of serum 25(OH)D and four potentially functional single nucleotide polymorphisms (SNPs) FokI, TaqI, VDR-5132, and Cdx2 in the VDR and their associated haplotypes with postmenopausal breast cancer risk. We additionally assessed effect modification of the association between 25(OH)D and breast cancer risk by the VDR polymorphisms.
 >Material and Methods
 >We used a population-based case-control study in Germany, which recruited incident breast cancer patients aged 50-74 between 2002 and 2005. Information on sociodemographic and breast cancer risk factors was collected by personal interview. Genotypes of SNPs were analyzed in 1406 cases and 2612 controls, matched on year of birth. Serum 25(OH)D was measured with an enzyme immunoassay in 1394 cases and 1365 controls, with additional matching on time of blood collection. Odds ratios for breast cancer adjusted for potential confounders were calculated for serum 25(OH)D, VDR genotypes and estimated haplotypes.
 >Results
 >Serum 25(OH)D concentration was significantly inversely associated with postmenopausal breast cancer risk. Compared with the lowest category (< 30 nM), odds ratios and 95% confidence intervals [OR (95% CI)] for the higher categories of 25(OH)D ( 30-45, 45-60, 60-75, >=75 nM) were 0.57 (0.45-0.73), 0.49 (0.38-0.64), 0.43 (0.32-0.57) and 0.31 (0.24-0.42), respectively (p_trend <0.0001). Analysis using fractional polynomials indicated a non-linear association. None of the analyzed polymorphisms was associated with overall risk of postmenopausal breast cancer. However, the TaqI polymorphism was associated with a significantly increased risk of estrogen receptor (ER) positive tumors [OR (95% CI)=1.18 (1.00-1.38), comparing t-allele carriers with non-carriers] but not of ER negative tumors [0.88 (0.69-1.13)] (p_interaction = 0.04). Haplotype analysis revealed the haplotype FtCA (FokI F, TaqI t, VDR-5132 C, Cdx2 A) to be associated with a significantly higher breast cancer risk compared to the most frequent haplotype FTCG [OR (95% CI)=1.43 (1.00-2.05)]. No significant interaction between VDR SNPs or haplotypes and 25(OH)D was observed.
 >Conclusion
 >Our findings strongly suggest a protective effect for postmenopausal breast cancer through a better vitamin D supply as characterized by serum 25(OH)D. However, potential effects of polymorphisms in the VDR were less evident and deserve further investigation.