O'Brien KM, et al. – This study was undertaken to analyze effect modification by single nucleotide polymorphisms (SNPs) in vitamin D–related genes. The association between serum 25(OH)D and breast cancer seemed to be modified by SNPs in vitamin D–related genes. These outcomes reinforced the evidence for protective effects of vitamin D.

Methods

• 50,884 US women who had a sister with breast cancer, but who had never had breast cancer themselves were part of the Sister Study.
• 1,524 women who developed breast cancer within 5 years to 1,810 randomly selected participants were compared by using a case-cohort design.
• Ratios of hazards ratios (RHRs) were computed for the 25(OH)D-breast cancer association per copy of the minor allele using Cox proportional hazards models.
• 82 SNPs were considered in 7 vitamin D-related genes (CYP24A1, CYP27B1, CYP2R1, GC, DHCR7/NADSYN1, RXRA, and VDR).
• Gene-based interactions with 25(OH)D, were examined.

Results

• Results indicated that 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.
• In addition, the minor allele was estimated to decrease the HR by 33% per copy (RHR=0.67, 95% confidence interval [CI]=0.53-0.85).
• Evidence of interaction at p<0.05 was demonstrated by five other VDR SNPs, as did one SNP in CYP2R1 and one in RXRA.
• Furthermore, evidence of multiplicative interaction with 25(OH)D (p=0.04) was portrayed by the 82 SNPs.
• Only VDR showed strong evidence of interaction (p=0.04), in gene-based tests.