Vitamin D Receptor Genetic Polymorphisms Are Associated with PSA Level, Gleason Score and Prostate Cancer Risk in African-American Men

Prostate cancer (PCa) is one of the most commonly diagnosed forms of cancer among men in the developed world (1, 2). In 2013, it was estimated that 238,590 men were diagnosed and 29,720 men died of PCa in the United States; and in 2014, there will be an estimated 1,665,540 new diagnosed cancer cases and 585,720 cancer deaths in the United States (3, 4). There are well-established risk-factors, such as genetic predisposition, age, ethnicity, family history, diet and environmental factors that contribute to the etiology of PCa (5). Additionally, there is a discrepancy in the risk of developing PCa among developed and underdeveloped countries and among ethnic groups. For example, the incidence and mortality rate of PCa in African-American (AA) is similar to men from the Caribbean and South America with West African ancestry. In the United States, though, there is a two-fold increased PCa incidence when comparing AA men with their Caucasian counterparts. Still, although epidemiological studies have shown that the incidence of PCa is lower in Asians, the occurrence of this disease has rapidly increased among Chinese men (6, 7). Such disproportionate difference in the prognosis and mortality of PCa among ethnic groups remains unclear. Prostate cell division is influenced by two steroid hormones: testosterone and vitamin D. The action of these hormones is mediated by their respective receptors: androgen receptor (AR) and vitamin D receptor (VDR). The hormonal active form of vitamin D 1, 25-dihydroxyvitamin D inhibits cancer cell growth angiogenesis and metastasis (8–11) and Vitamin D is one of the hormones that have been known to be associated with a lower risk of several types of cancer, including PCa (12–14). Vitamin D receptor, a nuclear transcription regulating factor that functions in signaling the synthesis of proteins involved in bone mineral homeostasis and cell-cycle regulation, mediates the action of vitamin D (14). The human VDR gene is found on chromosome 12q13.11 and is made up of 14 exons spanning approximately 75 kb (15, 16). It is highly polymorphic with at least 618 reported variants, most of which are either not detectable or at a low frequency in the general population, according to the dbSNP database (17). Previous studies have primarily focused on four common variants hypothesized to influence the expression and/or function of the VDR protein. Single nucleotide polymorphisms (SNPs) in the VDR gene, BsmI and FokI, have been inconsistently associated with breast cancer risk (18). Similarly identified SNPs in the VDR gene from population-based studies have also been associated with PCa risk (19–21, 21). Two SNPs, ApaI and BsmI, are located in intron 8, while TaqI is located in exon 9. Additionally, FokI is located in exon 2 and leads to a C/T substitution; its absence results in a truncated protein with greater luciferase activity (22). A G/A polymorphism in the promoter region of the VDR gene has also been shown to interact with the caudal related homeodomain transcription factor (CDX2); the common CDX2 G allele has 70% of the transcriptional activity compared with the A allele (23). Genetic polymorphisms and PCa association have been extensively studied generating mixed results (24–28), while some failed to conclude any positive associations of VDR polymorphisms and PCa (29–32). Because few studies have been performed in populations of African descent, we therefore embarked on a study to determine if DNA variation in VDR was associated with increased risk of PCa in AA men, as well as other clinical phenotypes, such as Gleason score. To test our hypothesis that VDR genotypes and haplotypes were indeed associated with PCa risk, we conducted a case-control study to determine the association of nine selected VDR SNPs with prostate specific antigen (PSA), Gleason Score and PCa risk.