A Prospective Study of Plasma Vitamin D Metabolites, Vitamin D Receptor Polymorphisms, and Prostate Cancer

Abstract

BackgroundVitamin D insufficiency is a common public health problem nationwide. Circulating 25-hydroxyvitamin D3 (25[OH]D), the most commonly used index of vitamin D status, is converted to the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D), which, operating through the vitamin D receptor (VDR), inhibits in vitro cell proliferation, induces differentiation and apoptosis, and may protect against prostate cancer. Despite intriguing results from laboratory studies, previous epidemiological studies showed inconsistent associations of circulating levels of 25(OH)D, 1,25(OH)2D, and several VDR polymorphisms with prostate cancer risk. Few studies have explored the joint association of circulating vitamin D levels with VDR polymorphisms.Methods and FindingsDuring 18 y of follow-up of 14,916 men initially free of diagnosed cancer, we identified 1,066 men with incident prostate cancer (including 496 with aggressive disease, defined as stage C or D, Gleason 7–10, metastatic, and fatal prostate cancer) and 1,618 cancer-free, age- and smoking-matched control participants in the Physicians' Health Study. We examined the associations of prediagnostic plasma levels of 25(OH)D and 1,25(OH)2D, individually and jointly, with total and aggressive disease, and explored whether relations between vitamin D metabolites and prostate cancer were modified by the functional VDR FokI polymorphism, using conditional logistic regression. Among these US physicians, the median plasma 25(OH)D levels were 25 ng/ml in the blood samples collected during the winter or spring and 32 ng/ml in samples collected during the summer or fall. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in 25(OH)D (<20 ng/ml) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels (<32 ng/ml). Plasma levels of 1,25(OH)2D did not vary by season. Men whose levels for both 25(OH)D and 1,25(OH)2D were below (versus above) the median had a significantly increased risk of aggressive prostate cancer (odds ratio [OR] = 2.1, 95% confidence interval [CI] 1.2–3.4), although the interaction between the two vitamin D metabolites was not statistically significant (p interaction = 0.23). We observed a significant interaction between circulating 25(OH)D levels and the VDR FokI genotype (p interaction < 0.05). Compared with those with plasma 25(OH)D levels above the median and with the FokI FF or Ff genotype, men who had low 25(OH)D levels and the less functional FokI ff genotype had increased risks of total (OR = 1.9, 95% CI 1.1–3.3) and aggressive prostate cancer (OR = 2.5, 95% CI 1.1–5.8). Among men with plasma 25(OH)D levels above the median, the ff genotype was no longer associated with risk. Conversely, among men with the ff genotype, high plasma 25(OH)D level (above versus below the median) was related to significant 60%∼70% lower risks of total and aggressive prostate cancer.ConclusionsOur data suggest that a large proportion of the US men had suboptimal vitamin D status (especially during the winter/spr...

Vitamin D Receptor Polymorphism and Cancer: An Update

“…Furthermore, studies have reported the association between VDR polymorphism with an increased risk of prostate cancer (36,38). However, the results of various studies were disputable and contradictory (39,40). Most of the studies found no association between VDR polymorphism and prostate cancer (13,22), however, Nunes et al found correlation between CC genotype (TaqI) with age (>58 years old), and GG (BsmI) with lower prostate-specific antigen (PSA) levels (<10 ng/ml) (41).…”

Vitamin D and prostate cancer risk: a review of the epidemiological literature

“…Men whose levels for both 25(OH)D and 1,25(OH)2D were below the median had a significantly increased risk of aggressive prostate cancer (OR ¼ 2.1, 95% CI ¼ 1.2-3.4), although the interaction between the two vitamin D metabolites was not statistically significant (P-interaction ¼ 0.23). 102 Another study examined a cohort of 3737 JapaneseAmerican men from 1967 to 1970, and after a surveillance period of over 23 years, the researchers identified 136 tissue-confirmed incident cases of prostate cancer. Their stored sera and those of 136 matched controls were measured for the following: 25(OH)D, 1,25(OH)2D, calcium, phosphorus and parathyroid hormone.…”

Lack of Association between Serum Levels of 25-Hydroxyvitamin D and the Subsequent Risk of Prostate Cancer in Finnish Men

“…Laboratory studies show that both the circulating form of vitamin D, 25-hydroxyvitamin D and the hormonal form 1,25-dihydroxyvitamin D, can inhibit the proliferation and invasiveness of prostate cancer cells in culture (6,7). Nevertheless, few large prospective epidemiology studies have supported the hypothesis that circulating levels of 25-hydroxyvitamin D are associated with the development of prostate cancer (8)(9)(10)(11)(12)(13)(14). Of the studies that have shown an inverse association, two were conducted in Nordic countries, where a significant percentage of the population is vitamin D deficient as measured by serum 25-hydroxyvitamin D levels (9,14).…”