| Vitamin D3 (VD3) is a fat soluble secosteroid obtained primarily through ultraviolet-B dependent synthesis in the skin. VD3 has antitumor effects and has been suggested to reduce risk of non-skin cancers. The vitamin D receptor (VDR) has shown inconsistent association with prostate cancer (PCa) risk. Mapping by admixture linkage disequilibrium (MALD) revealed a signal on chromosome 12 near the VDR gene. This dissertation project examines DNA sequence variation in the VDR promoter in three populations of men enrolled in PCa studies at two sites in the United States, Howard and Johns Hopkins Universities and one in Africa at the University of Benin Teaching Hospital in Nigeria. Samples from these sites were designated HU, JH, and N2 respectively. Ancestry informative markers (AIMs) on chromosome 12 were tested for association with PCa in a larger subset of HU samples. This study further investigates the association of AIMs with PCa in African Americans.;A total of 13 VDR promoter single nucleotide polymorphisms (SNPs), previously identified and novel, were characterized in the three populations. Two SNPs created activating transcription factor (ATF) and hunchback (Hb) binding sites. The number of SNPs for HU, N2, and JH populations equals 7, 4, and 2 respectively. Nucleotide diversity (pi) of the VDR promoter was greatest in the HU population, while Tajima's D, a measure of natural selection, was greatest in the N2 population. Analysis of molecular variance (AMOVA) estimates covariance (Ф) for subpopulation to total population ФST, subpopulation to continental group ФSC, and continental group to total population ФCT. This analysis shows that the largest contribution to total variance is due to variance within individuals.;The chromosome 12 AIM haplotype "ACCCC" was associated with PCa and high PSA by Chi square and logistic regression after adjusting for age and ancestry with an odds ratio (OR) of 4.34;95% CI, 1.746 -- 10.779; p = 0.0016. There was a higher mean percentage of West African Ancestry in cases compared to controls (73% vs. 67%) p = 0.047. This study identified a chromosome 12 AIM haplotype segregating with variants associated with the biology of PCa in African Americans.;... |
