Genetic variation in vitamin D-related genes among European and East Asian women and risk of breast cancer and risk according to breast tumour subtypes
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Vitamin D is hypothesized to decrease breast cancer risk by controlling cell proliferation, differentiation and apoptosis, and estrogen synthesis and signalling in breast tissue. Transport of circulating vitamin D to sites of action is facilitated by vitamin D binding protein, encoded by the GC gene, whereupon it binds to the vitamin D receptor, encoded by the VDR gene. Given that polymorphisms in the GC and VDR gene have not been consistently associated with breast cancer risk, our objectives were to assess the associations of vitamin D-related genes with overall, premenopausal and postmenopausal breast cancer risk; to determine these associations according to tumour receptor status; and, to assess associations between vitamin D receptor (VDR) haplotypes and breast cancer risk. A case-control study with 1,037 incident breast cancer cases and 1,050 age-frequency matched controls in Vancouver, British Columbia and Kingston, Ontario was conducted. Logistic regression in an additive genetic model was used to calculate age- and centre-adjusted odds ratios for associations between 21 single nucleotide polymorphisms (SNPs) of the GC and VDR gene and breast cancer risk. Polytomous regression was used to assess associations with breast tumour subtypes, and weighted logistic regression was conducted to calculate odds ratios for associations between VDR haplotypes and breast cancer risk. False discovery adjustments were made to address multiple testing. Among European women, two SNPs in the VDR gene, rs1544410 (OR = 0.38, 95% CI: 0.21 – 0.70) and rs7967152 (OR = 2.80, 95% CI: 1.62 – 4.85), were associated with risk of ER-/PR-/HER2+ breast tumour subtype, but not with other breast tumour subtypes. Although there were suggested associations with breast cancer risk for some SNPs and VDR haplotypes, there was no association after false discovery rate adjustment. In conclusion, breast tumour subtypes may be etiologically distinct disease states, with different risk factors and prognostic outcomes. Interactions between variations in vitamin D-related genes and breast tumour subtypes are biologically plausible given our current understanding of anti-carcinogenic properties of vitamin D elicited through the regulation of cell growth and reproductive hormone synthesis. Our findings provide additional insight into the etiologic differences among breast tumour subtypes.