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Background: Accumulating evidence suggests a role of vitamin D in preventing cancer development. Vitamin D through binding to vitamin D receptor (VDR) has been shown to exert regulatory effects on genes responsible for cell proliferation, differentiation, apoptosis, angiogenesis, and invasion. Common variation in VDR has been linked to risk for cancers including breast and colorectal cancers, although little is known about the variation in genes associated with vitamin D synthesis, transport, or downstream cofactors of vitamin D signaling in relation to cancer risk. While it is known that African Americans are more susceptible to vitamin D deficiency and to certain cancers, there is a lack of data targeting this ethnic group for the investigation of vitamin D-related genes and cancer events. Method: We performed a comprehensive evaluation of variation in 27 vitamin D-related genes in relation to total cancer events and site-specific cancer (breast and colorectal) from 8072 African American SHARe participants in the Women's Health Initiative (WHI) using the genome-wide SNP data from the Affymetrix 6.0 platform. As of 2009, a total of 957 women were identified with a confirmed diagnosis of cancer. Missing genotypes and remaining HapMap SNPs were imputed using MACH software with a 50:50 combination of YRI and CEU haplotypes as the reference sample. We conducted unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) as risk estimates for cancer with an additive model for each of the total 2159 (1590 imputed and 569 typed) SNPs with adjustment for age, geographic regions, cancer history, and potential population stratification by including the top 4 principal components of the ancestry estimates. A p-value of 0.0019 (0.05/number of genes) was denoted as statistical significance. All tests were two-sided. We had 80% power to detect an associated SNP with a minor allele frequency of 20% and a risk ratio of 1.85. Results: Two imputed SNPs, rs4853535 in the co-activator, STAT1, and rs2031455 in the synthesizer, TYRP1, were associated with total cancer risk (p≤0.001), whereas none of the typed SNPs reached statistical significance (p≥0.006). No association was also observed between the typed SNPs and breast cancer risk (N cases=447, p≥0.01). However, 2 typed SNPs that are in linkage disequilibrium (r2=0.85) residing in the synthesizer, MITF, were associated with colorectal cancer risk (N cases =137, ORs (95% CIs) were 1.92 (1.35, 2.73) and 2.02 (1.38-2.97), respectively for rs17638538 and rs2163326, p≤0.0008). Conclusion: Our study offers little support for an association between variation in vitamin D-related genes and total cancer risk in African American women. The risks associated with these genes are likely small and studies with larger sample size are required for such detection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5606. doi:10.1158/1538-7445.AM2011-5606