Vitamin D receptor gene polymorphisms, insulin-like growth factors, and prostate cancer risk: A population-based case-control study in China

Abstract

Background. Insulin-like growth factors (IGFs) have mitogenic and anti-apoptotic effects on prostate epithelial cells. Through modulation of IGF bioactivity, IGF binding proteins (IGFBPs) also have growth regulatory effects on prostate cells. Operating through the vitamin D receptor (VDR), vitamin D shows strong inhibitory effects on prostate cancer growth in both laboratory and human studies. Recent evidence indicates that vitamin D-induced prostate cancer inhibition is accompanied by increased IGFBP expression, suggesting that the vitamin D and IGF regulatory systems may operate together to affect prostate cancer. Methods. We sought to examine whether VDR gene polymorphisms affect prostate cancer risk -either independently or with plasma IGF or IGFBP levels - in a population-based case-control study in Shanghai, China. Histologically-confirmed cases of primary prostate cancer newly diagnosed between 1993 and 1995 (N = 191) and randomly selected age-matched population controls (N = 304) submitted to in-person interviews and blood draws. Genomic DNA was used to determine FokI and BsmI genotypes; IGF and IGFBP concentrations were determined from plasma. Results. No significant independent association of either the BsmI or the FokI VDR markers with prostate cancer was observed, though a small effect of BsmI cannot be ruled out owing to the low observed prevalence of its B allele. However, among men with the ff FokI genotype, those with the highest tertile of IGFBP-3 had a significantly decreased risk versus those with the lowest tertile (OR = 0.14; 95% CI = 0.04--0.56; ptrend < 0.01), while among men with the FF and Ff FokI genotypes IGFBP-3 was not associated with risk. Similarly, IGFBP-1 was significantly inversely associated with prostate cancer risk among men with the ff FokI genotype (OR = 0.25; 95% CI = 0.07--0.85; ptrend = 0.02), but not among men with the FF and Ff genotypes. No such FokI specific effects were noted for IGF-I or IGF-II. In addition, among population controls, IGF-II levels were significantly lower among those with the ff genotype versus the FF and Ff genotypes (p = 0.03), and IGFBP-1 levels appeared to increase with increasing copies of the f FokI allele. No associations between FokI genotype and levels of IGF-I of IGFBP-3 were observed. Conclusions. These findings in a low-risk population suggest that the IGF and vitamin D regulatory systems may interact to affect prostate cancer risk. Further studies are needed to confirm these findings and the clarify the underlying biological mechanisms.