Single-Nucleotide Polymorphisms in Vitamin D–Related Genes May Modify Vitamin D–Breast Cancer Associations

Abstract

Background We previously observed that high serum 25-hydroxyvitamin D [25(OH)D] (>38.0 ng/mL) was inversely associated with breast cancer. Here, we examined effect modification by single nucleotide polymorphisms (SNPs) in vitamin D-related genes. Methods The Sister Study enrolled 50,884 US women who had a sister with breast cancer, but who had never had breast cancer themselves. Using a case-cohort design, we compared 1,524 women who developed breast cancer within 5 years to 1,810 randomly selected participants. We estimated ratios of hazards ratios (RHRs) for the 25(OH)D-breast cancer association per copy of the minor allele using Cox proportional hazards models. We considered 82 SNPs in 7 vitamin D-related genes (CYP24A1, CYP27B1, CYP2R1, GC, DHCR7/NADSYN1, RXRA, and VDR). We also tested gene-based interactions with 25(OH)D. Results The SNP with the smallest interaction p-value was rs4328262 in VDR (p=0.0008); the 25(OH)D hazard ratio (HR) was 0.92 (95% confidence interval [CI]: 0.68–1.24) among those homozygous for the common allele, and the minor allele was estimated to decrease the HR by 33% per copy (RHR=0.67, 95% confidence interval [CI]=0.53–0.85). Five other VDR SNPs showed evidence of interaction at p<0.05, as did one SNP in CYP2R1 and one in RXRA. As a group, the 82 SNPs showed evidence of multiplicative interaction with 25(OH)D (p=0.04). In gene-based tests, only VDR showed strong evidence of interaction (p=0.04). Conclusions SNPs in vitamin D-related genes may modify the association between serum 25(OH)D and breast cancer. Impact This work strengthens the evidence for protective effects of vitamin D.

Genome-Wide Association Study of Serum 25-Hydroxyvitamin D in US Women

“…Serum samples were assessed for 25(OH)D concentrations using LC/MS at Heartland Assays, Inc. Measured concentrations were adjusted for batch effects and season of blood draw and thus approximate average annual 25(OH)D. Further details on both the SNP and 25(OH)D analysis can be found elsewhere (Amos et al, 2016 ; O'Brien et al, 2017a , b ).…”

“…The values of 25(OH)D looked normally distributed. We adjusted each model for age at blood draw (in years), self-reported race/ethnicity [Non-Hispanic White ( n = 1,576), Black ( n = 134), Hispanic ( n = 81), or other ( n = 38)] and genetic ancestry (proportion CEU, YRI, or CHB) (O'Brien et al, 2017a ) and calculated the genomic control inflation factor (λ) to test for evidence of uncontrolled confounding due to population stratification. We also conducted sensitivity analyses adjusting for estimated total vitamin D intake at baseline (dietary plus supplement) and hours spent outdoors per year, as these both contribute to variations in measured 25(OH)D concentrations.…”

Single Nucleotide Polymorphisms in 25-Hydroxyvitamin D3 1-Alpha-Hydroxylase (CYP27B1) Gene: The Risk of Malignant Tumors and Other Chronic Diseases

“…The breast tissue is the next place where the CYP27B1 enzyme is present, and thus also the next place where conversion to calcitriol occurs [85]. The results indicate a positive correlation between longer exposure to the sun and reduced breast cancer mortality [86,87], whereas the collected data indicate mixed results when it comes to the effects of diet or supplementation [88,89].…”

“…The polymorphism rs10877012 in another study was taken into account, as only polymorphisms with MAF below two percent were excluded; a study within this polymorphism showed an interaction with 25(OH)D levels in relation to breast cancer development [90]. As the authors point out, this gene may play a role in the prevention of cancer in individual cases, depending on the amount of UV-B radiation and the content of vitamin D in the diet [85]. The study conducted in the Swedish population showed no effect of the selected polymorphism within CYP27B1 (rs4646537) on risk of cancer, as well as no effect of any SNP within the VDR, CYP24A1, RXRA (retinoid X receptor alpha), GC/VDBP, 7-dehydrocholesterol reductase (DHCR7), and CYP2R1 genes (112 SNPs in total) [93].…”

No association of vitamin D binding protein gene polymorphisms with ulcerative colitis in Chinese patients

“…It is well known that VD is widely involved in a variety of biological activities in the body, especially chronic diseases. Polymorphisms in VD pathway-related genes have been extensively studied in cancer, chronic inflammation, autoimmune diseases, and lipid metabolism disorders [9,32,33]. In recent years, some studies have highlighted the importance of VD in the pathogenesis of IBD [34,35].…”