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

Date Published: March 20, 2007

Publisher: Public Library of Science

Author(s): Haojie Li, Meir J Stampfer, J. Bruce W Hollis, Lorelei A Mucci, J. Michael Gaziano, David Hunter, Edward L Giovannucci, Jing Ma, Eduardo L Franco

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 (pinteraction = 0.23). We observed a significant interaction between circulating 25(OH)D levels and the VDR FokI genotype (pinteraction < 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/spring season), and both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate cancer progression. Moreover, vitamin D status, measured by 25(OH)D in plasma, interacts with the VDR FokI polymorphism and modifies prostate cancer risk. Men with the less functional FokI ff genotype (14% in the European-descent population of this cohort) are more susceptible to this cancer in the presence of low 25(OH)D status.

Partial Text: Recent National Health and Nutrition Examination Survey (NHANES) data demonstrated that vitamin D insufficiency is a common public health problem nationwide, especially for elderly and minority populations [1]. A role for vitamin D in decreasing prostate cancer risk has been hypothesized on the basis of observations of higher prostate cancer mortality in regions of low solar radiation exposure and higher prostate cancer incidence in men of African descent, northern latitudes, and older age, all of which are associated with lower vitamin D status [2–4].

All baseline characteristics presented in Table 1 were similar between patients with prostate cancer and control participants. Of the 1,066 incident patients, 496 had aggressive disease, 539 had nonaggressive prostate cancer, and 31 were unable to be classified because of insufficient information. The median interval from baseline in 1982 to diagnosis was 11 y, and the average follow-up duration after diagnosis was 9 y.

In this large prospective cohort of middle-aged US male physicians, almost one-third of the men had vitamin D deficiency (25[OH]D <20 ng/ml), and more than two-thirds had insufficient vitamin D status (25[OH]D <32 ng/ml) in the winter/spring. Even in the summer/fall, more than 10% were vitamin D deficient, and more than half had insufficient vitamin D status (Table 1). These findings, consistent with most observations from other studies [16–22] as well as the recent NHANES [1], suggest an alarming problem of low vitamin D status in the US and in Northern European countries. Source:


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