The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements Comparative effects of dietary supplementation with red grape juice and vitamin E on production of superoxide by circulating neutrophil NADPH oxidase in hemodialysis patients. Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes? Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Serum Antioxidant Nutrients, Vitamin A, and Mortality in U.S. Adults Routine Vitamin Supplementation To Prevent Cancer and Cardiovascular Disease: Recommendations and Rationale Circulating 25OHD, dietary vitamin D, PTH, and calcium associations with incident cardiovascular disease and mortality: the MIDSPAN Family Study. Cardiovascular effects of oral Supplementation of vitamin C, E and folic acid in young healthy males. Vitamin/mineral supplementation and cancer, cardiovascular, and all-cause mortality in a German prospective cohort (EPIC-Heidelberg) Circulating Concentrations of Folate and Vitamin B12 in Relation to Prostate Cancer Risk: Results from the European Prospective Investigation into Cancer and Nutrition Study Vitamin Supplement Use During Breast Cancer Treatment and Survival: A Prospective Cohort Study Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT. Randomized controlled trial of vitamin D supplement on endothelial function in patients with type 2 diabetes. Circulating 25-Hydroxyvitamin D3 and Survival after Diagnosis with Kidney Cancer Effects of folate supplementation on two provisional molecular markers of colon cancer: a prospective, randomized trial Vitamin C Supplementation Decreases Oxidative Stress Biomarker F2-Isoprostanes in Plasma of Nonsmokers Exposed to Environmental Tobacco Smoke Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Adverse socioeconomic conditions in childhood and cause specific adult mortality: prospective observational study The association of biomarkers of iron status with mortality in US adults. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. Incidence of cancers, ischemic cardiovascular diseases and mortality during 5-year follow-up after stopping antioxidant vitamins and minerals supplements: a postintervention follow-up in the SU.VI.MAX Study. Circulating calcitriol concentrations and total mortality.
Background Low serum 25-hydroxyvitamin D [ 25(OH)D ] levels have been associated with higher risk of many diseases that affect mortality , including cardiovascular disease ( CVD ) and cancer . The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A , due to interactions of vitamin A at the level of the vitamin D nuclear receptor . In this prospect i ve cohort study , we investigated whether the association of 25(OH)D with all-cause , cancer , and CVD mortality  was modified by circulating vitamin A or preformed vitamin A intake from supplements . Methods We analyzed 15,998 adults in the Third National Health and Nutrition Examination Survey ( NHANES III ) , 1988–1994 . Mortality data for all-cause ( n = 3890 ) , cancer ( n = 844 ) , and CVD mortality ( n = 1715 ) were assessed through December 2006 .  Serum 25(OH)D was measured using a radioimmunoassay kit , vitamin A biomarkers were measured by HPLC , and information on supplement use was obtained by self-report . Multivariable hazard ratios ( HRs ) and corresponding 95 % confidence intervals ( CI ) were estimated by proportional hazards regression . Results Serum 25(OH)D was significantly inversely associated with all-cause mortality ( HR 0.93 , 95 % CI 0.89 , 0.97 , per 10 ng/mL increase ) and also with CVD mortality and mortality due to non-cancer/non-cardiovascular causes , but not with cancer mortality . The observed inverse associations remained statistically significant only among participants with serum retinyl esters < 7.0 μg/dL. High intake ( > 5000 IU/day ) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality . The observed interactions were not statistically significant . Conclusions 25(OH)D was inversely associated with overall mortality , CVD mortality , and mortality due to non-cancer/non-CVD causes , but not with cancer mortality . A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration BACKGROUND Atherosclerotic cardiovascular disease is the most common cause of death among hemodialysis patients ; it has been attributed to increased oxidative stress , dyslipidemia , malnutrition , and chronic inflammation . Activation of neutrophils is a well-recognized feature in dialysis patients , and superoxide-anion production by neutrophil NADPH oxidase may contribute significantly to oxidative stress . OBJECTIVE The aim of the study was to compare the effects of dietary supplementation with concentrated red grape juice ( RGJ ) , a source of polyphenols , and vitamin E on neutrophil NADPH oxidase activity and other cardiovascular risk factors in hemodialysis patients . DESIGN Thirty-two patients undergoing hemodialysis were recruited and r and omly assigned to groups to receive dietary supplementation with RGJ , vitamin E , or both or a control condition without supplementation or placebo . Blood was obtained at baseline and on days 7 and 14 of treatment . RESULTS RGJ consumption but not vitamin E consumption reduced plasma concentrations of total cholesterol and apolipoprotein B and increased those of HDL cholesterol . Both RGJ and vitamin E reduced plasma concentrations of oxidized LDL and ex vivo neutrophil NADPH oxidase activity . These effects were intensified when the supplements were used in combination ; in that case , reductions in the inflammatory biomarkers intercellular adhesion molecule 1 and monocyte chemoattractant protein 1 also were observed . CONCLUSIONS Regular ingestion of concentrated RGJ by hemodialysis patients reduces neutrophil NADPH-oxidase activity and plasma concentrations of oxidized LDL and inflammatory biomarkers to a greater extent than does that of vitamin E. This effect of RGJ consumption may favor a reduction in cardiovascular risk BACKGROUND Vitamin C acts as a potent antioxidant ; however , it can also be a prooxidant and glycate protein under certain circumstances in vitro . These observations led us to hypothesize that a high intake of vitamin C in diabetic persons might promote atherosclerosis . OBJECTIVE The objective was to examine the relation between vitamin C intake and mortality from cardiovascular disease . DESIGN We studied the relation between vitamin C intake and mortality from total cardiovascular disease ( n = 281 ) , coronary artery disease ( n = 175 ) , and stroke ( n = 57 ) in 1923 postmenopausal women who reported being diabetic at baseline .  Diet was assessed with a food-frequency question naire at baseline , and subjects initially free of coronary artery disease were prospect ively followed for 15 y. RESULTS After adjustment for cardiovascular disease risk factors , type of diabetes medication used , duration of diabetes , and intakes of folate , vitamin E , and beta-carotene , the adjusted relative risks of total cardiovascular disease mortality were 1.0 , 0.97 , 1.11 , 1.47 , and 1.84 ( P for trend < 0.01 ) across quintiles of total vitamin C intake from food and supplements . Adjusted relative risks of coronary artery disease were 1.0 , 0.81 , 0.99 , 1.26 , and 1.91 ( P for trend = 0.01 ) and of stroke were 1.0 , 0.52 , 1.23 , 2.22 , and 2.57 ( P for trend < 0.01 ) . When dietary and supplemental vitamin C were analyzed separately , only supplemental vitamin C showed a positive association with mortality endpoints .  Vitamin C intake was unrelated to mortality from cardiovascular disease in the nondiabetic subjects at baseline . CONCLUSION A high vitamin C intake from supplements is associated with an increased risk of cardiovascular disease mortality in postmenopausal women with diabetes BACKGROUND A meta- analysis of 19 trials suggested a small increase in the risk of all-cause mortality with high-dose vitamin E supplementation . Little is known , however , about the relation between mortality and circulating concentrations of vitamin E result ing from dietary intake , low-dose supplementation , or both . OBJECTIVE We examined whether baseline serum alpha-tocopherol concentrations are associated with total and cause-specific mortality . DESIGN A prospect i ve cohort study of 29 092 Finnish male smokers aged 50 - 69 y who participated in the Alpha-Tocopherol , Beta-Carotene Cancer Prevention ( ATBC ) Study was carried out . Fasting serum alpha-tocopherol was measured at baseline by using HPLC . Only 10 % of participants reported vitamin E supplement use at baseline , and thus serum concentrations of vitamin E mainly reflected dietary intake and other host factors . Risks of total and cause-specific mortality were estimated by using proportional hazards models . RESULTS During up to 19 y of follow-up , 13 380 deaths ( including 4518 and 5776 due to cancer and cardiovascular disease , respectively ) were identified . Men in the higher quintiles of serum alpha-tocopherol had significantly lower risks of total and cause-specific mortality than did those in the lowest quintile [ relative risk ( RR ) = 0.82 ( 95 % CI : 0.78 , 0.86 ) for total mortality and 0.79 ( 0.72 , 0.86 ) , 0.81 ( 0.75 , 0.88 ) , and 0.70 ( 0.63 , 0.79 ) for deaths due to cancer , cardiovascular disease , and other causes , respectively ; P for trend for all < 0.0001 ] . Cubic regression spline analysis of continuous serum alpha-tocopherol values indicated greater risk reductions with increasing concentrations up to approximately 13 - 14 mg/L , after which no further benefit was noted . CONCLUSION Higher circulating concentrations of alpha-tocopherol within the normal range are associated with significantly lower total and cause-specific mortality in older male smokers Background : Observational studies have suggested that antioxidant nutrients may reduce cancer and overall mortality risks . However , most r and omized trials have failed to show survival benefits . Examining nonlinear associations between antioxidant levels and health outcomes may help to explain these discrepant findings . Methods : We evaluated all-cause , cancer , and cardiovascular mortality risks associated with quintiles ( Q1–Q5 ) of serum antioxidant ( vitamins C and E , β-carotene , and selenium ) and vitamin A levels , in 16,008 adult participants of The Third National Health and Nutrition Examination Survey ( NHANES III ; 1988–1994 ) . Results : Over a median follow-up period of 14.2 years , there were 4,225 deaths , including 891 from cancer and 1,891 from cardiovascular disease . We observed a dose – response decrease in cancer and overall mortality risks with higher vitamin C levels . In contrast , for vitamin A , risk of cancer death decreased from Q1–Q2 , with no further decline in risk at higher levels . For vitamin E , having levels in Q4 was associated with the lowest cancer mortality risk . Both vitamin A and E had U-shaped associations with all-cause mortality . Cancer mortality risks decreased from Q1–Q2 for β-carotene and from Q1–Q4 for selenium . However , for β-carotene and selenium , overall mortality risks decreased from Q1–Q2 but then did not change significantly with higher levels . Conclusions : Antioxidant supplement use should be studied in the context of overall mortality and other competing mortality risks . Impact : These data suggest the need for novel intervention studies where doses of these agents are individualized based on their serum levels , and possibly , markers of oxidative stress and systemic inflammatory response . Cancer Epidemiol Biomarkers Prev ; 22(12 ) ; 2202–11 . © 2013 AACR Summary of the Recommendations The U.S. Preventive Services Task Force ( USPSTF ) concludes that the evidence is insufficient to recommend for or against the use of supplements of vitamins A , C , or E ; multivitamins with folic acid ; or antioxidant combinations for the prevention of cancer or cardiovascular disease . This is a grade I recommendation . ( See Appendix Table 1 for a description of the USPSTF classification of recommendations . ) The USPSTF found poor evidence to determine whether supplementation with these vitamins reduces the risk for cardiovascular disease or cancer . ( See Appendix Table 2 for a description of the USPSTF classification of levels of evidence . ) The available evidence from r and omized trials is either inadequate or conflicting , and the influence of confounding variables on observed outcomes in observational studies can not be determined . As a result , the USPSTF could not determine the balance of benefits and harms of routine use of supplements of vitamins A , C , or E ; multivitamins with folic acid ; or antioxidant combinations for the prevention of cancer or cardiovascular disease . The USPSTF recommends against the use of beta-carotene supplements , either alone or in combination , for the prevention of cancer or cardiovascular disease . This is a grade D recommendation . The USPSTF found good evidence that -carotene supplementation provides no benefit in the prevention of cancer or cardiovascular disease in middle-aged and older adults . In two trials restricted to heavy smokers , -carotene supplementation was associated with higher incidence of lung cancer and higher all-cause mortality . The USPSTF concludes that -carotene supplements are unlikely to provide important benefits and might cause harm in some groups . Clinical Considerations The USPSTF did not review evidence regarding vitamin supplementation for patients with known or potential nutritional deficiencies , including pregnant and lactating women , children , elderly persons , and people with chronic illnesses .  Dietary supplements may be appropriate for people whose diet does not provide the recommended dietary intake of specific vitamins . Individuals may wish to consult a health care provider to discuss whether dietary supplements are appropriate . With the exception of vitamins for which there is compelling evidence of net harm ( for example , beta-carotene supplementation in smokers ) , there is little reason to discourage people from taking vitamin supplements . Patients should be reminded that taking vitamins does not replace the need to eat a healthy diet . All patients should receive information about the benefits of a diet high in fruits and vegetables , as well as information on other foods and nutrients that should be emphasized or avoided in their diet ( see the 2002 USPSTF recommendations on counseling to promote a healthy diet [ 1 ] ) . Patients who choose to take vitamins  should be encouraged to adhere to the dosages recommended in the Dietary Reference Intakes of the Institute of Medicine . Some vitamins , such as A and D , may be harmful in higher doses ; therefore , doses greatly exceeding the Recommended Dietary Allowance or Adequate Intake should be taken with care while considering whether potential harms outweigh potential benefits . Vitamins and minerals sold in the United States are classified as dietary supplements , and there is a degree of quality control over content if they have a U.S. Pharmacopeia seal ( 2 ) . Nevertheless , imprecision in the content and concentration of ingredients could pose a theoretical risk not reflected in clinical trials using calibrated compounds . The adverse effects of beta-carotene on smokers have been observed primarily in those taking large supplemental doses . There is no evidence to suggest that beta-carotene is harmful to smokers at levels occurring naturally in foods . The USPSTF did not review evidence supporting folic acid supplementation among pregnant women to reduce neural tube defects . In 1996 , the USPSTF recommended folic acid for all women who are planning , or capable of , pregnancy ( see the 1996 USPSTF chapter on screening for neural tube defects [ 3 ] ) . Clinicians and patients should discuss the possible need for vitamin supplementation when taking certain medications ( for example , folic acid supplementation for patients taking methotrexate ) . Scientific Evidence The USPSTF review s ( 4 - 6 ) focused on the quality of the evidence regarding the effect of routine supplementation with certain vitamins on primary prevention of cancer and cardiovascular disease . These review s were undertaken because of the growing epidemiologic evidence that dietary factors may play a role in the etiology of these diseases ( 7 - 9 ) . The review s focused on prospect i ve trials of vitamin supplementation and observational studies of associations between the use of specific supplements and the risk for cancer or cardiovascular disease . The value of vitamins naturally occurring in food , the use of vitamin supplements for the prevention of other conditions ( for example , neural tube defects ) , and the use of vitamin supplements for the secondary prevention of complications in patients with existing disease were outside the scope of these review s. Vitamin A No prospect i ve trials have examined the effect of vitamin A supplements alone on the risk for cancer . Observational studies provide no evidence that such supplements prevent cancer in men . In women , observational studies have reported a statistically significant inverse association between use of vitamin A supplements and risk for colon and breast cancer ( 10 , 11 ) . Despite efforts to adjust for confounding variables , the observational , nonr and om design of these studies makes it difficult to assess the extent to which the reduced cancer risk is attributable to vitamin A or to other characteristics of women who take vitamin A supplements .  No evidence from prospect i ve trials is available regarding the benefits of vitamin A alone in preventing cardiovascular disease . One good- quality cohort study found no effect of vitamin A supplementation in reducing cardiovascular disease mortality ( 12 ) . Vitamin C No primary prevention trial of the effect of vitamin C supplementation alone on cancer or cardiovascular disease has been reported . Observational studies have generally shown no statistically significant associations between use of vitamin C supplements and risk for cancer of the breast , prostate , colon , or lung ( 12 - 14 ) . The observational cohort studies examining the effects of vitamin C on cardiovascular disease have produced inconsistent results ( 12 , 15 , 16 ) . Vitamin E Only a few trials have examined the effects of vitamin E on the primary prevention of cancer or cardiovascular disease . A r and omized , controlled trial ( RCT ) involving Finnish male smokers found that vitamin E supplementation is not protective against lung cancer but may have a beneficial impact on prostate cancer ( 14 ) . Because prostate cancer was not a primary end point of the trial and the trial had other limitations , further evidence is needed to confirm this finding . Observational studies have shown no statistically significant association between use of vitamin E supplements and risk for prostate , lung , or breast cancer ( 5 ) . One study suggested that vitamin E protects against colon cancer , but the influence of confounding variables can not be fully excluded ( 17 ) . Among primary prevention trials , two good- quality trials ( 14 , 18 ) and one fair- quality trial ( 19 ) found no statistically significant benefit of vitamin E supplementation in preventing cardiovascular disease ( 20 ) . Only one of seven trials of vitamin E supplementation for secondary prevention demonstrated a statistically significant reduction in cardiac events ( 4 ) . Some prospect i ve cohort studies have suggested a significant benefit , but the results are mixed and the influence of confounding variables can not be excluded ( 4 ) . -Carotene A consistent body of evidence from clinical trials suggests that beta-carotene supplementation does not decrease the risk for lung , prostate , colon , breast , or nonmelanoma skin cancer ( 14 , 21 - 25 ) . -Carotene supplements were associated with an increased risk for lung cancer among smokers , especially heavy smokers , in two RCTs ( 14 , 25 ) . Results from four RCTs demonstrated no reduced risk for cardiovascular events or death after beta-carotene supplementation ( 14 , 21 , 22 , 26 - 28 ) . Antioxidant Vitamin Combinations Studies of the effects of antioxidant vitamin combinations to prevent cancer have yielded mixed results . A recent RCT reported no statistically significant effect of daily supplementation with a combination of antioxidants : vitamin E , vitamin C , and beta-carotene ( 29 ) . Some studies have suggested an adverse effect of antioxidant combinations on cancer , but the results may have been confounded by the inclusion of beta-carotene ( 5 ) . Some observational studies of antioxidant vitamin combinations have suggested a benefit in preventing cardiovascular disease ( 13 , 30 , 31 ) , but other studies , including well- design ed RCTs , have shown no benefit ( 29 , 32 , 33 ) . One secondary prevention trial showed an increase in all-cause mortality among women taking antioxidant supplements  ( 34 ) . Multiple Vitamin Combinations The incremental benefit of taking supplemental doses of folic acid and B vitamins has been examined by comparing the outcomes of observational studies while controlling for the total intake of antioxidant vitamin supplements ( 35 ) . In these analyses , folic acid supplementation was associated with significantly decreased risk for colon cancer , but the protective effect requires confirmation in prospect i ve trials . There is conflicting evidence regarding the use of multivitamins and the risk for cardiovascular disease . Among cohort studies , one good- quality study reported a statistically significant reduction in coronary events ( 36 ) , two good- quality studies reported no statistically significant effect on mortality ( 16 , 37 ) , and one CONTEXT Observational studies relating circulating 25-hydroxyvitamin D ( 25OHD ) and dietary vitamin D intake to cardiovascular disease ( CVD ) have reported conflicting results . OBJECTIVE Our objective was to investigate the association of 25OHD , dietary vitamin D , PTH , and adjusted calcium  with  CVD and mortality in a Scottish cohort . DESIGN AND SETTING The MIDSPAN Family Study is a prospect i ve study of 1040 men and 1298 women from the West of Scotl and recruited in 1996 and followed up for a median 14.4 yr . PARTICIPANTS Locally resident adult offspring of a general population cohort were recruited from 1972 - 1976 . MAIN OUTCOME MEASURES CVD events ( n = 416 ) and all-cause mortality ( n = 100 ) were evaluated . RESULTS 25OHD was measured using liquid chromatography-t and em mass spectrometry in available plasma ( n = 2081 ) . Median plasma 25OHD was 18.6 ng/ml , and median vitamin D intake was 3.2 μg/d ( 128 IU/d ) . Vitamin D deficiency ( 25OHD < 15 ng/ml ) was present in 689 participants ( 33.1 % ) . There was no evidence that dietary vitamin D intake , PTH , or adjusted calcium were associated with CVD events or with mortality . Vitamin D deficiency was not associated with CVD ( fully adjusted hazard ratio = 1.00 ; 95 % confidence interval = 0.77 - 1.31 ) . Results were similar after excluding patients who reported an activity-limiting longst and ing illness at baseline ( 18.8 % ) and those taking any vitamin supplements ( 21.7 % ) . However , there was some evidence vitamin D deficiency was associated with all-cause mortality ( fully adjusted hazard ratio = 2.02 ; 95 % confidence interval = 1.17 - 3.51 ) . CONCLUSION Vitamin D deficiency was not associated with risk of CVD in this cohort with very low 25OHD . Future trials of vitamin D supplementation in middle-aged cohorts should be powered to detect differences in mortality outcomes as well as CVD Numerous observational studies showed associations of antioxidants ( vitamins C and E ) and folate intake with a reduced risk of cardiovascular disease , but r and omized controlled clinical trials have generally not supported this hypothesis . The objective of this study was to investigate the effects of a daily dosage of 1000 mg vitamin C , 800 mg vitamin E , and 10 mg folate on markers of vascular function in 31 young healthy male adults .  Cardiovascular values after a 12-week vitamin ( 14 subjects ) or placebo ( 17 subjects ) intervention were compared to baseline values . Cardiovascular parameters ( blood pressure , stroke volume , heart rate , cardiac output , vascular resistance , arterial compliance ) were measured continuously after an overnight fast under controlled circumstances with a Finometer device . Our main finding was a significant decrease ( p = 0.03 ) in systolic blood pressure in the experimental group . No statistically significant changes were observed within other cardiovascular variables of the experimental group , but possible beneficial decreases in diastolic blood pressure and increases in arterial compliance after 12 weeks of vitamin supplementation were indicated . In conclusion , beneficial effects of antioxidants and folate were observed probably because the supplementation was used by young healthy subjects under carefully controlled conditions Purpose To prospect ively evaluate the association of vitamin/mineral supplementation with  cancer , cardiovascular , and all-cause mortality .  Methods In the Heidelberg cohort of the European Prospect i ve Investigation into Cancer and Nutrition ( EPIC-Heidelberg ) , which was recruited in 1994–1998 , 23,943 participants without pre-existing cancer and myocardial infa rct ion/stroke at baseline were included in the analyses . Vitamin/mineral supplementation was assessed at baseline and during follow-up . Cox regression models were used to estimate hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) . Results After an average follow-up time of 11 years , 1,101 deaths were documented ( cancer deaths = 513 and cardiovascular deaths = 264 ) . After adjustment for potential confounders , neither any vitamin/mineral supplementation nor multivitamin supplementation at baseline was statistically significantly associated with cancer , cardiovascular , or all-cause mortality . However , baseline users of antioxidant vitamin supplements had a significantly reduced risk of cancer mortality ( HR : 0.52 ; 95 % CI : 0.28 , 0.97 ) and all-cause mortality ( HR : 0.58 ; 95 % CI : 0.38 , 0.88 ) . In comparison with never users , baseline non-users who started taking vitamin/mineral supplements during follow-up had significantly increased risks of cancer mortality ( HR : 1.74 ; 95 % CI : 1.09 , 2.77 ) and all-cause mortality ( HR : 1.58 ; 95 % CI : 1.17 , 2.14 ) . Conclusions Based on limited numbers of users and cases , this cohort study suggests that supplementation of antioxidant vitamins might possibly reduce cancer and all-cause mortality . The significantly increased risks of cancer and all-cause mortality among baseline non-users who started taking supplements during follow-up may suggest a “ sick-user effect , ” which research ers should be cautious of in future observational studies Background : Determinants of one-carbon metabolism , such as folate and vitamin B12 , have been implicated in cancer development . Previous studies have not provided conclusive evidence for the importance of circulating concentrations of folate and vitamin B12 in prostate cancer etiology . The aim of the present study was to investigate the relationship between prostate cancer risk and circulating concentrations of folate and vitamin B12 in a large prospect i ve cohort . Methods : We analyzed circulating concentrations of folate and vitamin B12 in 869 cases and 1,174 controls , individually matched on center , age , and date of recruitment , nested within the European Prospect i ve Investigation into Cancer and Nutrition cohort .  Relative risks ( RR ) for prostate cancer were estimated using conditional logistic regression models . Results : Overall , no significant associations were observed for circulating concentrations of folate ( Ptrend = 0.62 ) or vitamin B12 ( Ptrend = 0.21 ) with prostate cancer risk . RRs for a doubling in folate and vitamin B12 concentrations were 1.03 [ 95 % confidence interval ( 95 % CI ) , 0.92 - 1.16 ] and 1.12 ( 95 % CI , 0.94 - 1.35 ) , respectively . In the subgroup of cases diagnosed with advanced stage prostate cancer , elevated concentrations of vitamin B12 were associated with increased risk ( RR for a doubling in concentration , 1.69 ; 95 % CI , 1.05 - 2.72 , Ptrend = 0.03 ) . No other subgroup analyses result ed in a statistically significant association . Conclusion : This study does not provide strong support for an association between prostate cancer risk and circulating concentrations of folate or vitamin B12 . Elevated concentrations of vitamin B12 may be associated with an increased risk for advanced stage prostate cancer , but this association requires examination in other large prospect i ve studies . ( Cancer Epidemiol Biomarkers Prev 2007;17(2):279–85 Background : Antioxidants may protect normal cells from the oxidative damage that occurs during radiotherapy and certain chemotherapy regimens ; however , the same mechanism could protect tumor cells and potentially reduce effectiveness of cancer treatments . We evaluated the association of vitamin supplement use in the first 6 months after breast cancer diagnosis and during cancer treatment with total mortality and recurrence . Methods : We conducted a population -based prospect i ve cohort study of 4,877 women aged 20 to 75 years diagnosed with invasive breast cancer in Shanghai , China , between March 2002 and April 2006 . Women were interviewed approximately 6 months after diagnosis and followed up by in-person interviews and record linkage with the vital statistics registry . Results : During a mean follow-up of 4.1 years , 444 deaths and 532 recurrences occurred . Vitamin use shortly after breast cancer diagnosis was associated with reduced mortality and recurrence risk , adjusted for multiple lifestyle factors , sociodemographics , and known clinical prognostic factors . Women who used antioxidants ( vitamin E , vitamin C , multivitamins ) had 18 % reduced mortality risk ( HR = 0.82 , 95 % CI : 0.65–1.02 ) and 22 % reduced recurrence risk ( HR = 0.78 , 95 % CI : 0.63–0.95 ) . The inverse association was found regardless of whether vitamin use was concurrent or nonconcurrent with chemotherapy , but was present only among patients who did not receive radiotherapy . Conclusions : Vitamin supplement use in the first 6 months after breast cancer diagnosis may be associated with reduced risk of mortality and recurrence . Impact : Our results do not support the current recommendation that breast cancer patients should avoid use of vitamin supplements . Cancer Epidemiol Biomarkers Prev ; 20(2 ) ; 262–71 . © 2010 AACR BACKGROUND Although basic research suggests that vitamins may have an important role in the prevention of cardiovascular diseases ( CVD ) , the data from cohort studies and clinical trials are inconclusive . METHODS This prospect i ve cohort study was conducted among 83 639 male physicians residing in the United States who had no history of CVD or cancer . At baseline , data on use of vitamin E , ascorbic acid ( vitamin C ) , and multivitamin supplements were provided by a self-administered question naire . Mortality from CVD and coronary heart disease ( CHD ) was assessed by death certificate review . RESULTS Use of supplements was reported by 29 % of the participants . During a mean follow-up of 5.5 years , 1037 CVD deaths occurred , including 608 CHD deaths . After adjustment for several cardiovascular risk factors , supplement use was not significantly associated with total CVD or CHD mortality . For vitamin E use , the relative risks ( RRs ) were 0.92 ( 95 % confidence interval [ CI ] , 0.70 - 1.21 ) for total CVD mortality and 0.88 ( 95 % CI , 0.61 - 1.27 ) for CHD mortality ; for use of vitamin C , the RRs were 0.88 ( 95 % CI , 0.70 - 1.12 ) for total CVD mortality and 0.86 ( 95 % CI , 0.63 - 1.18 ) for CHD mortality ; and for use of multivitamin supplements , the RRs were 1.07 ( 95 % CI , 0.91 - 1.25 ) for total CVD mortality and 1.02 ( 95 % CI , 0.83 - 1.25 ) for CHD mortality . CONCLUSIONS In this large cohort of apparently healthy US male physicians , self-selected supplementation with vitamin E , vitamin C , or multivitamins was not associated with a significant decrease in total CVD or CHD mortality . Data from ongoing large r and omized trials will be necessary to definitely establish small potential benefits of vitamin supplements on subsequent cardiovascular risk CONTEXT Observational studies show an association between low vitamin D status assessed by circulating 25-hydroxyvitamin D and cardiovascular events and mortality . Data from r and omized controlled trials are limited . OBJECTIVE The aim of this study was to test whether daily doses of vitamin D(3 ) at 400 or 1000 IU/d for 1 yr affected conventional markers of cardiovascular disease ( CVD ) risk . DESIGN We conducted a parallel-group , double-blind , placebo-controlled r and omized controlled trial . R and omization was computer generated . Participants and study investigators were blinded to intervention groupings throughout the trial . SETTING The study was conducted at the Clinical Research Facility , University of Aberdeen , United Kingdom . PARTICIPANTS A total of 305 healthy postmenopausal women aged 60 - 70 yr were recruited for the study . INTERVENTION Each woman received a daily capsule of 400 or 1000 IU vitamin D(3 ) or placebo r and omly allocated . MAIN OUTCOME MEASURES Primary outcomes were serum lipid profile [ total , high-density lipoprotein , and low-density lipoprotein cholesterol ; triglycerides ; and apolipoproteins A-1 and B100 ] , insulin resistance ( homeostatic model assessment ) , inflammatory biomarkers ( high-sensitivity C-reactive protein , IL-6 , soluble intracellular adhesion molecule-1 ) , and blood pressure . RESULTS A total of 265 ( 87 % ) participants completed all study visits . Small differences between groups for serum apolipoprotein B100 change [ repeated measures ANOVA , P=0.04 ; mean ( sd ) , -1.0 ( 10.0 ) mg/dl ( 400 IU ) ; -1.0 ( 10.0 ) mg/dl ( 1000 IU ) ; and + 0.02 ( 10.0 ) mg/dl ( placebo ) ] were not considered clinical ly significant . Other systemic markers for CVD risk remained unchanged . There was significant seasonal variation in systolic and diastolic blood pressure independent of vitamin D dose ( P<0.001 , linear mixed model ) . Mean ( sd ) reduction in systolic blood pressure from winter to summer was -6.6 ( 10.8 ) mm Hg . CONCLUSIONS Improving vitamin D status through dietary supplementation is unlikely to reduce CVD risk factors . Confounding of seasonality should be recognized and addressed in future studies of vitamin BACKGROUND Suboptimal vitamin D status is associated with endothelial dysfunction and an increased risk of cardiovascular diseases but it is unclear whether vitamin D supplementation is beneficial . The aim was to investigate the effect of vitamin D supplementation on endothelial function in patients with type 2 diabetes mellitus ( DM ) . METHODS In a double-blind , placebo-controlled trial , we r and omized 100 type 2 DM patients to vitamin D supplement  ( 5000 IU/day , n = 50 ) or placebo ( controls , n = 50 ) for 12 weeks . Assessment of vascular function with brachial artery flow-mediated dilatation ( FMD ) , circulating levels of endothelial progenitor cells ( EPCs ) and brachial-ankle pulse wave velocity , and metabolic parameter , high-sensitivity C-reactive protein ( hsCRP ) and oxidative stress markers were performed before and after the supplementation . RESULTS After 12 weeks , vitamin D treated patients had significant increases in serum 25-hydroxyvitamin D [ 25(OH)D ] concentration ( treatment effect 34.7 ng/mL , 95 % CI 26.4 - 42.9 , P < 0.001 ) and serum ionized calcium ( treatment effect 0.037 mmol/L , 95 % CI 0.007 - 0.067 , P = 0.018 ) ; decreased serum parathyroid hormone concentration ( treatment effect -0.55 pmol/L , 95 % CI -1.08 to -0.02 , P = 0.042 ) compared to patients who received placebo . Nevertheless , vitamin D supplementation did not improve vascular function as determined by FMD , circulating EPC count or baPWV ( all P > 0.05 ) . Furthermore , hsCRP , oxidative stress markers , low- and high-density lipoprotein and glycated hemoglobin were also similar between two groups ( all P > 0.05 ) . CONCLUSION In patients with type 2 DM , 12 weeks oral supplementation of vitamin D did not significantly affect vascular function or serum biomarkers of inflammation and oxidative stress . CLINICAL TRIAL NUMBER HKCTR-867 , www.hk clinical trials.com Prospect i ve cohort studies have provided some evidence that circulating vitamin D is associated with risk of , and survival from , renal cell carcinoma ( RCC ) , but it is unclear whether concentrations of vitamin D at the time of diagnosis of RCC are associated with prognosis . We conducted a case – cohort study of 630 RCC cases , including 203 deaths , from a multicenter case – control study in Eastern Europe .  Vitamin D was assessed as 25-hydroxyvitamin D3 [ 25(OH)D3 ] , and we used weighted Cox models to estimate hazard ratios ( HR ) and 95 % confidence intervals ( CI ) by categories of season-adjusted 25(OH)D3 . Higher concentrations of 25(OH)D3 were associated with lower risk of death after adjusting for stage , age , sex , and country ( HR highest vs. lowest category 0.57 ; 95 % CI , 0.34–0.97 ) . The inverse associations of 25(OH)D3 with death were most notable among those who died from non-RCC causes and those diagnosed with early-stage disease . In summary , 25(OH)D3 concentration at diagnosis of RCC was inversely associated with all-cause mortality rates , but not specifically with RCC outcome . Cancer Epidemiol Biomarkers Prev ; 24(8 ) ; 1277–81 . © 2015 AACR OBJECTIVES : Dietary folate intake is inversely associated with the risk of colorectal cancer . This study investigated the effect of folate supplementation on genomic DNA methylation and DNA str and breaks in exons 5–8 of the p53 gene of the colonic mucosa , two provisional biomarkers of colon cancer . METHODS : Twenty subjects with adenomas were r and omized to receive either folate ( 5 mg/day ) or placebo for 1 yr after polypectomy . At baseline , 6 months and 1 yr , systemic and colonic measures of folate status were determined , as were the biomarkers mentioned earlier . RESULTS : Folate supplementation increased serum , red blood cell and colonic mucosal folate concentrations ( p < 0.02 ) . Folate supplementation also increased the extent of genomic DNA methylation at 6 months and 1 yr ( p = 0.001 ) , whereas placebo administration was associated with an increase in the extent of genomic DNA methylation only at 1 yr . Similarly , folate supplementation decreased the extent of p53 str and breaks in exons 5–8 at 6 months and 1 yr ( p < 0.02 ) , whereas placebo administration was associated with a decrease in the extent of p53 str and breaks only at 1 yr . CONCLUSIONS : Both of these provisional biomarkers of colon cancer underwent accelerated improvement at 6 months with folate supplementation . However , these markers also improved with placebo at 1 yr . Therefore , potential confounding factors that seem to modulate these biomarkers need to be identified and corrected in order for these markers to serve as suitable surrogate endpoints in folate chemoprevention trials Exposure to environmental tobacco smoke ( ETS ) has been linked to increased risk of lung cancer and cardiovascular diseases in nonsmokers . Current research suggests that some of these diseases are associated with elevated oxidative stress . We investigated the effect of antioxidant ( AO ) intervention on the lipid peroxidation biomarker F2-isoprostanes ( F2-IsoPs ) , an index of oxidative stress , in plasma of nonsmokers exposed to ETS ( passive smokers).We measured free F2-IsoP concentrations in plasma of 67 passive smokers at baseline and after 2 mo of daily intervention with AOs or placebo .  The study subjects ( 47 females , 20 males ; mean age 46 ± 15 ) were r and omized into one of three treatment groups : vitamin C , " mixture " ( vitamin C , vitamin E , and α-lipoic-acid ) , and placebo . Investigated confounders included plasma baseline AO levels , lipid and total cholesterol profiles , transferrin saturation , and C-reactive protein . Plasma F2IsoP concentrations of subjects in the vitamin C and mixture groups decreased significantly by 17.2 pmol/l ( P = 0.0105 ) and 19.2 pmol/l ( P = 0.0083 ) when compared with the placebo group ( 11.4 % and 12.7 % , respectively ) . Daily AO supplementation ( especially with vitamin C ) decreases this oxidative stress biomarker in passive smokers . This finding might be of importance for the prevention of ETS-associated adverse health effects in nonsmokers BACKGROUND Frequent use of personal , non protocol calcium supplements obscured an adverse effect of coadministered calcium and vitamin D ( CaD ) on cardiovascular risk in the Women 's Health Initiative ( WHI ) . OBJECTIVE We investigated the effects of the use of personal calcium or vitamin D supplements on other outcomes in the WHI CaD Study ( WHI CaD ) by using the WHI limited-access clinical trials data set . DESIGN The WHI CaD was a 7-y , r and omized , placebo-controlled trial of CaD ( 1 g Ca/400 IU vitamin D daily ) in 36,282 community-dwelling , postmenopausal women . The incidence of total cancer ( excluding nonmelanoma skin cancers ) , breast and colorectal cancers , hip and total fracture , and mortality was assessed by using Cox proportional hazards models . RESULTS In the WHI CaD , interactions between the use of either personal calcium or vitamin D supplements and CaD were found for total , breast , and colorectal cancers but not for fracture or mortality .  In 15,646 women ( 43 % ) who were not taking personal calcium or vitamin D supplements at r and omization , CaD significantly decreased the risk of total , breast , and invasive breast cancers by 14 - 20 % and nonsignificantly reduced the risk of colorectal cancer by 17 % . In women taking personal calcium or vitamin D supplements , CaD did not alter cancer risk ( HR : 1.06 - 1.26 ) . CONCLUSIONS For women in the WHI CaD who were not taking personal calcium or vitamin D supplements at r and omization , CaD decreased the risk of total , breast , and colorectal cancers and did not change the risk of fractures or total mortality . The nonskeletal effects of CaD may be more important than the skeletal effects and should be considered when evaluating these supplements . The WHI CaD trial is registered at clinical trials.gov as NCT00000611 Abstract Objective : To investigate the association between social circumstances in childhood and mortality from various causes of death in adulthood . Design : Prospect i ve observational study . Setting : 27 workplaces in the west of Scotl and . Subjects : 5645 men aged 35–64 years at the time of examination . Main outcome measures : Death from various causes . Results : Men whose fathers had manual occupations when they were children were more likely as adults to have manual jobs and be living in deprived areas . Gradients in mortality from coronary heart disease , stroke , lung cancer , stomach cancer , and respiratory disease were seen ( all P<0.05 ) , generally increasing from men whose fathers had professional and managerial occupations ( social class I and II ) to those whose fathers had semiskilled and unskilled manual occupations ( social class IV and V ) . Relative rates of mortality adjusted for age for men with fathers in manual versus non-manual occupations were 1.52 ( 95 % confidence interval 1.24 to 1.87 ) for coronary heart disease , 1.83 ( 1.13 to 2.94 ) for stroke , 1.65 ( 1.12 to 2.43 ) for lung cancer , 2.06 ( 0.93 to 4.57 ) for stomach cancer , and 2.01 ( 1.17 to 3.48 ) for respiratory disease . Mortality from other cancers and accidental and violent death showed no association with fathers ' social class . Adjustment for adult socioeconomic circumstances and risk factors did not alter results for mortality from stroke and stomach cancer , attenuated the increased risk of coronary heart disease and respiratory disease , and essentially eliminated the association with lung cancer . Conclusions : Adverse socioeconomic circumstances in childhood have a specific influence on mortality from stroke and stomach cancer in adulthood , which is not due to the continuity of social disadvantage throughout life . Deprivation in childhood influences risk of mortality from coronary heart disease and respiratory disease in adulthood , although an additive influence of adulthood circumstances is seen in these cases . Mortality from lung cancer , other cancer , and accidents and violence is predominantly influenced by risk factors that are related to social circumstances in adulthood . Key messages Adverse socioeconomic conditions in childhood are associated with mortality in later life Mortality from stroke and stomach cancer is particularly dependent on social circumstances in childhood Mortality from coronary heart disease and respiratory disease is dependent on social circumstances in both adulthood and childhood Mortality from accidents and violence and from lung cancer is mainly dependent on factors acting in adulthood The increases in child poverty seen in Britain and elsewhere over the past 20 years may herald unfavourable future trends in adult BACKGROUND AND AIMS Elevated iron biomarkers are associated with diabetes and other cardiometabolic abnormalities in the general population . It is unclear whether they are associated with an increased risk of all-cause or cause-specific mortality . The purpose of the current analysis was to evaluate the association of  ferritin and transferrin saturation levels with  all-cause , cardiovascular , and cancer mortality in the general US adult population . METHODS AND RESULTS A prospect i ve cohort study was conducted with 12,258 adults participating in the Third National Health and Nutrition Examination Survey ( NHANES III ) , a nationally representative sample of the US population . Study participants were recruited in 1988 - 1994 and followed through December 31 , 2006 for all-cause , cardiovascular disease , and cancer mortality .  The multivariable-adjusted hazard ratios ( 95 % confidence interval ) for all-cause mortality comparing the fourth versus the second quartiles of ferritin and transferrin saturation were 1.09 ( 0.82 - 1.44 ; p-trend across quartiles = 0.92 ) and 1.08 ( 0.82 - 1.43 ; p-trend across quartiles = 0.62 ) , respectively , for men , 1.43 ( 0.63 - 3.23 ; p-trend across quartiles = 0.31 ) and 1.48 ( 0.70 - 3.11 ; p-trend across quartiles = 0.60 ) , respectively , for premenopausal women , and 1.03 ( 0.79 - 1.34 ; p-trend across quartiles = 0.95 ) and 1.17 ( 0.92 - 1.49 ; p-trend across quartiles = 0.63 ) , respectively , for postmenopausal women . Quartile of ferritin and transferrin saturation also showed no association between biomarkers of iron status and mortality . CONCLUSIONS In a large nationally representative sample of US adults , within the spectrum of normal iron metabolism , ferritin and transferrin saturation were not associated with risk of mortality among people who were not taking iron supplements and did not have a baseline history of cardiovascular disease or cancer CONTEXT Basic research provides plausible mechanisms and observational studies suggest that apparently healthy persons , who self-select for high intakes of vitamin E through diet or supplements , have decreased risks of cardiovascular disease and cancer . R and omized trials do not generally support benefits of vitamin E , but there are few trials of long duration among initially healthy persons . OBJECTIVE To test whether vitamin E supplementation decreases risks of cardiovascular disease and cancer among healthy women . DESIGN , SETTING , AND PARTICIPANTS In the Women 's Health Study conducted between 1992 and 2004 , 39 876 apparently healthy US women aged at least 45 years were r and omly assigned to receive vitamin E or placebo and aspirin or placebo , using a 2 x 2 factorial design , and were followed up for an average of 10.1 years . INTERVENTION Administration of 600 IU of natural- source vitamin E on alternate days . MAIN OUTCOME MEASURES Primary outcomes were a composite end point of first major cardiovascular event ( nonfatal myocardial infa rct ion , nonfatal stroke , or cardiovascular death ) and total invasive cancer . RESULTS During follow-up , there were 482 major cardiovascular events in the vitamin E group and 517 in the placebo group , a nonsignificant 7 % risk reduction ( relative risk [ RR ] , 0.93 ; 95 % confidence interval [ CI ] , 0.82 - 1.05 ; P = .26 ) . There were no significant effects on the incidences of myocardial infa rct ion ( RR , 1.01 ; 95 % CI , 0.82 - 1.23 ; P = .96 ) or stroke ( RR , 0.98 ; 95 % CI , 0.82 - 1.17 ; P = .82 ) , as well as ischemic or hemorrhagic stroke . For cardiovascular death , there was a significant 24 % reduction ( RR , 0.76 ; 95 % CI , 0.59 - 0.98 ; P = .03 ) . There was no significant effect on the incidences of total cancer ( 1437 cases in the vitamin E group and 1428 in the placebo group ; RR , 1.01 ; 95 % CI , 0.94 - 1.08 ; P = .87 ) or breast ( RR , 1.00 ; 95 % CI , 0.90 - 1.12 ; P = .95 ) , lung ( RR , 1.09 ; 95 % CI , 0.83 - 1.44 ; P = .52 ) , or colon cancers ( RR , 1.00 ; 95 % CI , 0.77 - 1.31 ; P = .99 ) . Cancer deaths also did not differ significantly between groups . There was no significant effect of vitamin E on total mortality ( 636 in the vitamin E group and 615 in the placebo group ; RR , 1.04 ; 95 % CI , 0.93 - 1.16 ; P = .53 ) . CONCLUSIONS The data from this large trial indicated that 600 IU of natural- source vitamin E taken every other day provided no overall benefit for major cardiovascular events or cancer , did not affect total mortality , and decreased cardiovascular mortality in healthy women . These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women The Supplementation in Vitamins and Mineral Antioxidants Study was a double-blind , placebo-controlled , r and omized trial , in which 12,741 French adults ( 7,713 women aged 35 - 60 years and 5,028 men aged 45 - 60 years ) received a combination of ascorbic acid ( 120 mg ) , vitamin E ( 30 mg ) , beta-carotene ( 6 mg ) , selenium ( 100 microg ) and zinc ( 20 mg ) , or placebo daily for a median follow-up time of 7.5 years [ October 1994 to September 2002 ] . Antioxidant supplementation decreased total cancer incidence and total mortality in men . Postintervention follow-up assessment of total cancer incidence , ischemic cardiovascular disease incidence and total mortality was carried out for 5 years [ September 1 , 2002 , to September 1 , 2007 ] . No late effect of antioxidant supplementation  was revealed 5 years after ending the intervention neither on ischemic cardiovascular disease incidence and mortality in both genders nor on cancer incidence in women . Regarding duration of intervention effects in men , the reduced risk of total cancer incidence and total mortality was no longer evident after the 5-year postintervention follow-up . During the postsupplementation period , the relative risk ( RR ) for total cancer incidence ( n = 126 ) was 0.98 ( 95 % confidence interval [ CI ] , 0.75 - 1.27 ) among antioxidant recipients compared to nonrecipients . For total mortality ( n = 90 ) , the RR was 0.98 ( 95 % CI , 0.75 - 1.26 ) for men receiving antioxidants compared to nonrecipients . In conclusion , beneficial effects of antioxidant supplementation in men disappeared during postintervention follow-up BACKGROUND Evidence is accumulating that vitamin D supplementation of patients with low 25-hydroxyvitamin D concentrations is associated with lower cardiovascular morbidity and total mortality during long-term follow-up . Little is known , however , about the effect of low concentrations of the vitamin D hormone calcitriol on total mortality . We therefore evaluated the predictive value of circulating calcitriol for midterm mortality in patients of a specialized heart center . METHODS This prospect i ve cohort study included 510 patients , 67.7 % with heart failure ( two-thirds in end stage ) , 64.3 % hypertension , 33.7 % coronary heart disease , 20.2 % diabetes , and 17.3 % renal failure . We followed the patients for up to 1 year after blood collection . For data analysis , the study cohort was stratified into quintiles of circulating calcitriol concentrations . RESULTS Patients in the lowest calcitriol quintile were more likely to have coronary heart disease , heart failure , hypertension , diabetes , and renal failure compared to other patients . They also had low 25-hydroxyvitamin D concentrations and high concentrations of creatinine , C-reactive protein , and tumor necrosis factor alpha . Eighty-two patients ( 16.0 % ) died during follow-up . Probability of 1-year survival was 66.7 % in the lowest calcitriol quintile , 82.2 % in the second quintile , 86.7 % in the intermediate quintile , 88.8 % in the fourth quintile , and 96.1 % in the highest quintile ( P < 0.001 ) . Discrimination between survivors and nonsurvivors was best when a cutoff value of 25 ng/L was applied ( area under the ROC curve 0.72 ; 95 % CI 0.66 - 0.78 ) . CONCLUSIONS Decreased calcitriol levels are linked to excess midterm mortality in patients of a specialized heart center
Subgroup analyses in the observational studies indicated that risk of mortality was significantly higher in studies with lower baseline use of vitamin D supplements .
The effects observed for vitamin D3 supplementation remained unchanged when grouped by various characteristics .
However , for vitamin D2 supplementation , increased risks of mortality were observed in studies with lower intervention doses and shorter average intervention periods .
Conclusions Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease , cancer , and other causes .
Objective To evaluate the extent to which circulating biomarker and supplements of vitamin D are associated with  mortality from cardiovascular , cancer , or other conditions  , under various circumstances .