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A prospective study of plasma vitamin D metabolites , vitamin D receptor polymorphisms , and prostate cancer . BACKGROUND Vitamin 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 FINDINGS During 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 % approximately 70 % lower risks of total and aggressive prostate cancer . CONCLUSIONS Our 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 .
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Intervention_Pharmacological
plasma vitamin D metabolites
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Intervention_Pharmacological
vitamin D receptor polymorphisms
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Intervention_Pharmacological
25-hydroxyvitamin D3 ( 25 [ OH ] D )
30328
Intervention_Pharmacological
25 ( OH ) D
30329
Intervention_Pharmacological
1,25 ( OH ) 2D
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Intervention_Pharmacological
vitamin D status
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Intervention_Pharmacological
VDR FokI polymorphism
30332
Outcome_Physical
median plasma 25 ( OH ) D levels
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Outcome_Physical
25 ( OH ) D
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Outcome_Physical
plasma 25 ( OH ) D levels
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Outcome_Physical
Plasma levels of 1,25 ( OH ) 2D
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Outcome_Physical
risk of aggressive prostate cancer
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Outcome_Physical
25 ( OH ) D levels
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Outcome_Physical
VDR FokI genotype
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Outcome_Physical
plasma 25 ( OH ) D levels
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Outcome_Physical
risks of total
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Outcome_Physical
aggressive prostate cancer
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Outcome_Physical
plasma 25 ( OH ) D levels
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Outcome_Physical
high plasma 25 ( OH ) D level
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Outcome_Physical
risks of total and aggressive prostate cancer
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Outcome_Physical
25 ( OH ) D in plasma