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1.  Serum Levels of Vitamin D Metabolites and Breast Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 
Experimental and epidemiologic studies suggest that vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)2D] and its precursor 25-hydroxyvitamin D [25(OH)D]) may reduce breast cancer risk. We examined subsequent breast cancer risk related to serum levels of these metabolites. In a cohort of women ages 55 to 74 years, who donated blood at baseline (1993–2001) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we identified 1,005 incident breast cancer cases during follow-up through 2005 (mean time between blood draw and diagnosis, 3.9 years). Noncases (n = 1,005) were frequency matched to the cases based on age and year of entry. Sample weights that accounted for unequal probabilities of selecting cases and noncases were applied to make inferences that reflected the entire Prostate, Lung, Colorectal, and Ovarian cohort. Using Cox proportional hazards modeling, we computed breast cancer relative risks (RR) and 95% confidence intervals (95% CI) by quintile for each metabolite. The RR of breast cancer for the highest quintile of 25(OH)D concentration versus the lowest was 1.04 (95% CI, 0.75–1.45; Ptrend = 0.81). Similarly, the breast cancer RR for the highest quintile of 1,25(OH)2D compared with the lowest was 1.23 (95% CI, 0.91–1.68; Ptrend = 0.14). Excluding the first 2 years of follow-up did not materially alter these estimates. There was also no evidence of inverse risk in older women (≥60 years) versus younger women (<60 years). In this prospective study of postmenopausal women, we did not observe an inverse association between circulating 25(OH)D or 1,25(OH)2D and breast cancer risk, although we cannot exclude an association in younger women or with long-term or earlier exposure.
doi:10.1158/1055-9965.EPI-07-2594
PMCID: PMC4039037  PMID: 18381472
2.  Vitamin D Status in Neonates Undergoing Cardiac Operations: Relationship to Cardiopulmonary Bypass and Association with Outcomes 
The Journal of pediatrics  2012;162(4):823-826.
Objectives
To determine the incidence of vitamin D deficiency in neonates with congenital heart disease and whether differences exist by race. In addition, we determined the effect of cardiopulmonary bypass on vitamin D levels, and explored associations between 25-hydroxyvitamin D [25(OH)D] levels and postoperative outcomes.
Study design
A secondary analysis of a prospective randomized controlled trial in 70 neonates undergoing cardiac surgery was performed. 25(OH)D levels were collected in the operating room prior to skin incision (baseline), at the cessation of cardiopulmonary bypass and 24 hours post-operatively. Associations between these levels and clinical outcomes were explored. Vitamin D deficiency was defined as a 25(OH)D level <20 ng/ml.
Results
Vitamin D deficiency was present in 84% (59/70); concentrations in African-Americans (n=20) were significantly lower than Caucasian/other (n=50) (10.2 ±4.2ng/ml vs. 16.0 ±5.6ng/ml, p<0.0001). The 24 hour postoperative 25(OH)D level were not different from baseline and correlated with a reduced postoperative inotropic requirement (r=−0.316, p=0.008).
Conclusions
Vitamin D deficiency is prevalent in neonates with congenital cardiac defects and lower postoperative 25(OH)D levels are associated with the need for increased inotropic support in neonates undergoing cardiac operations. These findings provide support that vitamin D deficiency may play a role in myocardial injury and postoperative recovery and warrants further investigation.
doi:10.1016/j.jpeds.2012.10.013
PMCID: PMC3578094  PMID: 23149171
congenital heart disease; heart surgery; vitamin deficiency
3.  Associations of serum 25-Hydroxyvitamin D with overall and breast cancer-specific mortality in a multi-ethnic cohort of breast cancer survivors 
Cancer causes & control : CCC  2013;24(4):759-767.
Purpose
Despite limited evidence on the association of vitamin D with outcomes in breast cancer survivors, some clinicians advise breast cancer patients to use vitamin D supplements. More evidence is needed to inform these recommendations.
Methods
In the Health, Eating, Activity and Lifestyle Study, we examined associations of post-treatment serum concentrations of 25-hydroxyvitamin D (25(OH)D) on overall and breast-cancer-specific mortality in 585 breast cancer survivors from western Washington State, New Mexico, and Los Angeles County. 25(OH)D was measured in stored blood collected 2 years post-enrollment. Outcomes were ascertained from the Surveillance, Epidemiology, and End Results registries and medical records. Cox proportional hazards models were fit to assess associations of serum 25(OH)D with overall and breast-cancer-specific mortality.
Results
After a median follow-up of 9.2 years; 110 women died, including 48 from breast cancer. Standard cut points classified 211 (31.6%) women as serum 25(OH)D deficient (<20 ng/mL), 189 (32.2%) as insufficient (20–30 ng/mL), and 185 (36.2%) as sufficient (>30 ng/mL). Compared to women with deficient 25(OH)D, those in the sufficient ranges had a decreased risk of overall mortality (age-adjusted HR=0.58; 95%CI 0.36–0.96); however multivariate adjustments attenuated the association (HR=0.90; 95%CI 0.50–1.61). No association was found between serum 25(OH)D and breast-cancer-specific mortality (sufficient: HR=1.21; 95%CI 0.52–2.80) in multivariate models.
Conclusion
In this breast cancer cohort, higher serum 25(OH)D may be associated with improved survival, but results were not statistically significant and must be interpreted with caution. The potential prognostic effect of vitamin D from diet, supplements or both should be evaluated in future larger studies with additional endpoints from breast cancer patients.
doi:10.1007/s10552-013-0158-4
PMCID: PMC3731052  PMID: 23361338
25-hydroxyvitamin D; overall mortality; breast-cancer-specific mortality; vitamin D
4.  Assessment and Interpretation of Circulating 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D in the Clinical Environment 
doi:10.1016/j.ecl.2010.02.012
PMCID: PMC2903449  PMID: 20511051
vitamin D; 25-hydroxyvitamin D; 1,25-dihydroxyvitamin D; calcidiol; calcitriol
5.  Vitamin D Deficiency in Critically Ill Children 
Pediatrics  2012;130(3):421-428.
OBJECTIVE:
Vitamin D influences cardiovascular and immune function. We aimed to establish the prevalence of vitamin D deficiency in critically ill children and identify factors influencing admission 25-hydroxy vitamin D (25(OH)D) levels. We hypothesized that levels would be lower with increased illness severity and in children with serious infections.
METHODS:
Participants were 511 severely or critically ill children admitted to the PICU from November 2009 to November 2010. Blood was collected near PICU admission and analyzed for 25(OH)D concentration by using Diasorin radioimmunoassay.
RESULTS:
We enrolled 511 of 818 (62.5%) eligible children. The median 25(OH)D level was 22.5 ng/mL; 40.1% were 25(OH)D deficient (level <20 ng/mL). In multivariate analysis, age and race were associated with 25(OH)D deficiency; summer season, vitamin D supplementation, and formula intake were protective; 25(OH)D levels were not lower in the 238 children (46.6%) admitted with a life-threatening infection, unless they had septic shock (n = 51, 10.0%) (median 25(OH)D level 19.2 ng/mL; P = .0008). After adjusting for factors associated with deficiency, lower levels were associated with higher admission day illness severity (odds ratio 1.19 for a 1-quartile increase in Pediatric Risk of Mortality III score per 5 ng/mL decrease in 25(OH)D, 95% confidence interval 1.10–1.28; P < .0001).
CONCLUSIONS:
We found a high rate of vitamin D deficiency in critically ill children. Given the roles of vitamin D in bone development and immunity, we recommend screening of those critically ill children with risk factors for vitamin D deficiency and implementation of effective repletion strategies.
doi:10.1542/peds.2011-3328
PMCID: PMC4074622  PMID: 22869836
critical care; vitamin D; septic shock
6.  Vitamin D status and impact of vitamin D3 and/or calcium supplementation in a randomized pilot study in the southeastern U.S.* 
Objective
Vitamin D supplementation may be required for certain subgroups in the U.S. in whom status and intake is inadequate, but the impact of various doses, and whether calcium administration jointly or independently influences vitamin D metabolite levels, is unclear.
Methods
In a pilot chemoprevention trial of biomarkers of risk for colorectal adenoma, we measured the impact of vitamin D supplementation, and/or calcium supplementation, on plasma vitamin D metabolite concentrations. Ninety-two adult men and women living in the southeastern U.S. were randomized to either 800 IU vitamin D3, 2,000 mg elemental calcium, both, or placebo daily for six months. We examined vitamin D status at baseline and post-intervention, and compared the change in plasma 25(OH)D and 1,25(OH)2D levels by intervention group using general linear models.
Results
Eighty-two percent (%) of the study population had insufficient plasma 25(OH)D concentrations (< 75 nmol/L) at baseline, with lowest levels among African American participants. Vitamin D supplements, with or without calcium supplementation, raised plasma 25(OH)D concentrations, on average, 25 - 26 nmol/L. Half of study participants were classified as having sufficient 25(OH)D status after six months of 800 IU vitamin D3 daily. Calcium alone did not influence 25(OH)D concentrations.
Conclusion
In this southeastern U.S. population, half of the study participants receiving 800 IU vitamin D3 daily had blood 25(OH)D concentrations of ≤ 75 nmol/L after a six-month intervention period, supporting higher vitamin D dose requirements estimated by some groups. More research is needed to identify the optimal vitamin D dose to improve 25(OH)D status in various at-risk populations.
PMCID: PMC3731379  PMID: 20516268
7.  A Prospective Study of 25-Hydroxy-Vitamin D and Risk of Myocardial Infarction in Men 
Archives of internal medicine  2008;168(11):1174-1180.
Background
Vitamin D deficiency may be involved in the development of atherosclerosis and coronary heart disease (CHD) in humans. We assessed prospectively whether plasma 25(OH)vitamin D (25(OH)D) concentrations are associated with risk of CHD.
Methods
A nested case-control study was conducted among 18,225 male participants of the Health Professionals Follow-up Study aged 40 to 75 years who were free of diagnosed cardiovascular disease at the time of blood draw (1993–1995). During 10 years of follow-up through January 31, 2004, 454 men developed MI (nonfatal myocardial infarction) or fatal CHD. Using risk set sampling, controls were selected in a 2:1 ratio matched for age, date of blood draw, and smoking status (n=900).
Results
After adjustment for matched variables, men deficient (≤15 ng/mL) in 25(OH)D were at increased risk of MI compared to those considered to be sufficient (≥30 ng/mL) in 25(OH)D (relative risk (RR)=2.42; 95% confidence interval (CI), 1.53–3.84; P for trend <.001). After additional adjustment for family history of MI, body mass index, alcohol consumption, physical activity, history of diabetes and hypertension, ethnicity, region, marine omega-3 intake, low- and high-density lipoprotein cholesterol and triglyceride levels, this relationship remained significant (RR=2.09; 95% CI, 1.24–3.54; P for trend=0.02). Even men with intermediate values for 25(OH)D were at elevated risk relative to those with sufficient 25(OH)D (22.6–29.9 ng/mL: RR=1.60; 95% CI, 1.10–2.32; 15.0–22.5 ng/mL: RR=1.43; 95% CI, 0.96–2.13).
Conclusions
This study provides evidence that optimal levels of 25(OH)D should be at least 30 ng/mL to lower risk of MI.
doi:10.1001/archinte.168.11.1174
PMCID: PMC3719391  PMID: 18541825
8.  Serum Vitamin D Concentration and Prostate Cancer Risk: a Nested Case–Control Study 
Background
Epidemiological studies have yielded inconsistent associations between vitamin D status and prostate cancer risk, and few studies have evaluated whether the associations vary by disease aggressiveness. We investigated the association between vitamin D status, as determined by serum 25-hydroxy-vitamin D [25(OH)D] level, and risk of prostate cancer in a case–control study nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.
Methods
The study included 749 case patients with incident prostate cancer who were diagnosed 1 to 8 years after blood draw and 781 control subjects who were frequency-matched by age at cohort entry, time since initial screening, and calendar year of cohort entry. All study participants were selected from the trial screening arm (which includes annual standardized prostate cancer screening). Conditional logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) by quintile of 25(OH)D. Statistical tests were two-sided.
Results
No statistically significant trend in overall prostate cancer risk was observed with increasing serum season-standardized 25(OH)D level. However, serum 25(OH)D concentrations greater than the lowest quintile (Q1) associated with increased risk of aggressive (Gleason sum ≥7 or clinical stage III or IV) disease (ORs for Q2 vs Q1 = 1.20, 95% CI = 0.80 to 1.81, for Q3 vs Q1 =1.96, 95% CI = 1.34 to 2.87, for Q4 vs Q1 = 1.61, 95% CI = 1.09 to 2.38, and for Q5 vs Q1 = 1.37, 95% CI = 0.92 to 2.05; Ptrend = .05). The rates of aggressive prostate cancer for increasing quintiles of serum 25(OH)2D were 406, 479, 780, 633, and 544 per 100,000 person-years. In exploratory analyses, these associations with aggressive disease were consistent across subgroups defined by age, family history of prostate cancer, diabetes, body mass index, vigorous physical activity, calcium intake, study center, season of blood collection, and assay batch.
Conclusion
The findings of this large prospective study do not support the hypothesis that vitamin D is associated with decreased risk of prostate cancer; indeed, higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease.
doi:10.1093/jnci/djn152
PMCID: PMC3703748  PMID: 18505967
25-hydroxy-vitamin D; prostate cancer
10.  Vitamin D–Related Genetic Variation, Plasma Vitamin D, and Risk of Lethal Prostate Cancer: A Prospective Nested Case–Control Study 
Background
The association of vitamin D status with prostate cancer is controversial; no association has been observed for overall incidence, but there is a potential link with lethal disease.
Methods
We assessed prediagnostic 25-hydroxyvitamin D [25(OH)D] levels in plasma, variation in vitamin D–related genes, and risk of lethal prostate cancer using a prospective case–control study nested within the Health Professionals Follow-up Study. We included 1260 men who were diagnosed with prostate cancer after providing a blood sample in 1993–1995 and 1331 control subjects. Men with prostate cancer were followed through March 2011 for lethal outcomes (n = 114). We selected 97 single-nucleotide polymorphisms (SNPs) in genomic regions with high linkage disequilibrium (tagSNPs) to represent common genetic variation among seven vitamin D–related genes (CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, and VDR). We used a logistic kernel machine test to assess whether multimarker SNP sets in seven vitamin D pathway–related genes were collectively associated with prostate cancer. Tests for statistical significance were two-sided.
Results
Higher 25(OH)D levels were associated with a 57% reduction in the risk of lethal prostate cancer (highest vs lowest quartile: odds ratio = 0.43, 95% confidence interval = 0.24 to 0.76). This finding did not vary by time from blood collection to diagnosis. We found no statistically significant association of plasma 25(OH)D levels with overall prostate cancer. Pathway analyses found that the set of SNPs that included all seven genes (P = .008) as well as sets of SNPs that included VDR (P = .01) and CYP27A1 (P = .02) were associated with risk of lethal prostate cancer.
Conclusion
In this prospective study, plasma 25(OH)D levels and common variation among several vitamin D–related genes were associated with lethal prostate cancer risk, suggesting that vitamin D is relevant for lethal prostate cancer.
doi:10.1093/jnci/djs189
PMCID: PMC3341310  PMID: 22499501
11.  Racial variation in vitamin D cord blood concentration in White and Black male neonates 
Cancer causes & control : CCC  2012;24(1):91-98.
Background
To evaluate racial variation in umbilical cord blood concentration of vitamin D and to explore its correlation with markers of the insulin-like growth factor axis (IGFs) and sex steroid hormones in white and black male neonates.
Methods
In 2004/2005 venous umbilical cord blood samples were collected from 75 black and 38 white male neonates, along with maternal and birth characteristics from two hospitals in Maryland, US. 25-hydroxyvitamin D [25(OH)D], and 1,25-dihydroxyvitamin D [1,25(OH)2D] were measured by radioimmunoassay (RIA), testosterone, estradiol and sex hormone binding globulin (SHBG) by immunoassay and IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP-3) by ELISA. Crude and multivariable-adjusted geometric mean concentrations were computed.
Results
Mean 25(OH)D levels were lower in black than in white neonates (11.44; 95% CI 10.10–12.95 ng/mL vs. 18.24; 95% CI 15.32–21.72 ng/mL; p<0.0001). Black neonates were at higher risk of suboptimal vitamin D levels [25(OH)D < 20 ng/mL] than whites (84% vs. 63%). 25(OH)D concentrations varied by season in whites but not in blacks and were significantly inversely correlated with mother’s parity (number of live births) in blacks but not in whites. Mean concentration of 1,25(OH)2D did not differ by race. 25(OH)D and 1,25(OH)2D did not correlate with IGFs, sex steroid hormones and SHBG.
Conclusions
Suboptimal vitamin D levels were prevalent especially in blacks and influenced by mother’s parity and by season. The observed vitamin D differences between black and white neonates warrant further evaluation of the etiology of the disparity in chronic diseases in adulthood.
doi:10.1007/s10552-012-0093-9
PMCID: PMC3529856  PMID: 23139102
Vitamin D; umbilical cord blood; black and white Americans
12.  Vitamin D Is Required for IFN-γ–Mediated Antimicrobial Activity of Human Macrophages 
Science Translational Medicine  2011;3(104):104ra102.
Control of tuberculosis worldwide depends on our understanding of human immune mechanisms, which combat the infection. Acquired T cell responses are critical for host defense against microbial pathogens, yet the mechanisms by which they act in humans remain unclear. We report that T cells, by the release of interferon-γ (IFN-γ), induce autophagy, phagosomal maturation, the production of antimicrobial peptides such as cathelicidin, and antimicrobial activity against Mycobacterium tuberculosis in human macrophages via a vitamin D–dependent pathway. IFN-γ induced the antimicrobial pathway in human macrophages cultured in vitamin D–sufficient sera, but not in sera from African-Americans that have lower amounts of vitamin D and who are more susceptible to tuberculosis. In vitro supplementation of vitamin D–deficient serum with 25-hydroxyvitamin D3 restored IFN-γ–induced antimicrobial peptide expression, autophagy, phagosome-lysosome fusion, and antimicrobial activity. These results suggest a mechanism in which vitamin D is required for acquired immunity to overcome the ability of intracellular pathogens to evade macrophage-mediated antimicrobial responses. The present findings underscore the importance of adequate amounts of vitamin D in all human populations for sustaining both innate and acquired immunity against infection.
doi:10.1126/scitranslmed.3003045
PMCID: PMC3269210  PMID: 21998409
13.  Vitamin D Supplementation during Pregnancy: Double Blind, Randomized Clinical Trial of Safety and Effectiveness 
Background
The need, safety and effectiveness of vitamin D supplementation during pregnancy remain controversial.
Design
In this randomized controlled trial, women with a singleton pregnancy at 12–16 weeks’ gestation received 400, 2000 or 4000 IU vitamin D3/day until delivery. The primary outcome was maternal/neonatal circulating 25(OH)D at delivery, with secondary outcomes 25(OH)D ≥80 nmol/L achieved and 25(OH)D concentration required to achieve maximal 1,25(OH)2D production.
Results
Of the 494 women enrolled, 350 women continued until delivery: Mean 25(OH)D by group at delivery and 1-month before delivery were significantly different (p<0.0001), and percent who achieved sufficiency was significantly different by group, greatest in 4000 IU group (p<0.0001). The relative risk (RR) for achieving ≥80 nmol/L within one month of delivery was significantly different between 2000 vs. 400 IU (RR 1.52 [CI 1.24–1.86]); 4000 vs. 400 (RR 1.60 [CI 1.32–1.95]), but not between 4000 vs. 2000 (RR 1.06 [CI 0.93–1.19]). Circulating 25(OH)D had a direct influence on circulating 1,25(OH)2D concentrations throughout pregnancy (p<0.0001) with maximal production of 1,25(OH)2D in all strata in the 4000 IU group. There were no differences between groups on any safety measure. Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels.
Conclusions
Vitamin D supplementation of 4,000 IU/day for pregnant women was safe and most effective in achieving sufficiency in all women and their neonates regardless of race while the current estimated average requirement was comparatively ineffective at achieving adequate circulating 25(OH)D, especially in African Americans.
doi:10.1002/jbmr.463
PMCID: PMC3183324  PMID: 21706518
14.  A Seven Day Continuous Infusion of PTH or PTHrP Suppresses Bone Formation and Uncouples Bone Turnover 
Journal of Bone and Mineral Research  2011;26(9):2287-2297.
Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM) or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed seven-day continuous infusion models using hPTH(1–34) and hPTHrP(1–36) in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dl), with marked suppression of endogenous PTH(1–84). The maximal tolerated infused doses over a seven-day period (2 and 4 pmol/kg/hr, for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8–28 pmol/kg/hr). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25(OH)2D and TmP/GFR remained unaltered with these low doses, despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly, and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30–40% for the seven days of the infusions. With cessation of PTH and PTHrP infusion, bone formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone resorption program, but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions is reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT.
doi:10.1002/jbmr.415
PMCID: PMC3304443  PMID: 21544866
Parathyroid Hormone; PTH-Related Protein; Humoral Hypercalcemia of Malignancy; Hyperparathyroidism; Lactation
15.  Circulating levels of vitamin D and colon and rectal cancer: the Physicians’ Health Study and a meta-analysis of prospective studies 
It remains unknown whether increased risk with low levels of vitamin D is present for colon and/or rectal cancer. To investigate the association between circulating vitamin D levels and colon and rectal cancer, we examined the associations between plasma levels of 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) and colon and rectal cancer in the Physicians’ Health Study and then conducted a meta-analysis of eight prospective studies of circulating levels of 25-hydroxyvitamin D (25(OH)D) and colon and rectal cancers, including the Physicians’ Health Study. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using a random-effects model. A total of 1822 colon and 868 rectal cancers were included in the meta-analysis. We observed a significant inverse association for colorectal cancer (OR = 0.66; 95% CI = 0.54–0.81), comparing top versus bottom quantiles of circulating 25(OH)D levels. The inverse association was stronger for rectal cancer (OR = 0.50 for top versus bottom quantiles; 95% CI = 0.28–0.88) than colon cancer (OR = 0.77; 95% CI = 0.56–1.07; P for difference between colon and rectal cancer = 0.20). These data suggest an inverse association between circulating 25(OH)D levels and colorectal cancer, with a stronger association for rectal cancer.
doi:10.1158/1940-6207.CAPR-10-0289
PMCID: PMC3412303  PMID: 21430073
16.  Maternal Vitamin D and Fetal Growth in Early-Onset Severe Preeclampsia 
Objective
Recently vitamin D deficiency has been associated with increased risks for preeclampsia and diagnosis of early-onset, severe preeclampsia (EOSPE). The purpose of this investigation was to examine the association between vitamin D levels and small for gestational age (SGA) in patients with EOSPE.
Study Design
Patients with EOSPE were recruited and demographics, outcomes, and plasma were collected. 25-hydroxy-vitamin D (25-OH-D) was assessed by radioimmunoassay and reported in ng/mL. Results were analyzed by Mann Whitney U test and Spearman correlation and reported as median (Q1–Q3).
Results
In patients with EOSPE (n=56), 25-OH-D was lower in patients with SGA (16.8 ng/mL [8.9–23]) verses normal fetal growth (25.3 ng/mL [16–33]) (p=0.02). 25-OH-D was significantly correlated with percentile growth at delivery (ρ = 0.31, p=0.02).
Conclusions
Vitamin D is lower among patients with SGA in EOSPE than those without growth retardation. We suspect that vitamin D may impact fetal growth through placental mechanisms.
doi:10.1016/j.ajog.2011.03.022
PMCID: PMC3136573  PMID: 21507371
25-hydroxyvitamin D; fetal growth restriction; preeclampsia; Vitamin D; small for gestational age (SGA)
17.  Vitamin D Status in Patients With Stage IV Colorectal Cancer: Findings From Intergroup Trial N9741 
Journal of Clinical Oncology  2011;29(12):1599-1606.
Purpose
Previous studies have suggested that higher plasma 25-hydroxyvitamin D3 [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival, but the prevalence of vitamin D deficiency in advanced colorectal cancer and its influence on outcomes are unknown.
Patients and Methods
We prospectively measured plasma 25(OH)D levels in 515 patients with stage IV colorectal cancer participating in a randomized trial of chemotherapy. Vitamin D deficiency was defined as 25(OH)D lower than 20 ng/mL, insufficiency as 20 to 29 ng/mL, and sufficiency as ≥ 30 ng/mL. We examined the association between baseline 25(OH)D level and selected patient characteristics. Cox proportional hazards models were used to calculate hazard ratios (HR) for death, disease progression, and tumor response, adjusted for prognostic factors.
Results
Among 515 eligible patients, 50% of the study population was vitamin D deficient, and 82% were vitamin D insufficient. Plasma 25(OH)D levels were lower in black patients compared to white patients and patients of other race (median, 10.7 v 21.1 v 19.3 ng/mL, respectively; P < .001), and females compared to males (median, 18.3 v 21.7 ng/mL, respectively; P = .0005). Baseline plasma 25(OH)D levels were not associated with patient outcome, although given the distribution of plasma levels in this cohort, statistical power for survival analyses were limited.
Conclusion
Vitamin D deficiency is highly prevalent among patients with stage IV colorectal cancer receiving first-line chemotherapy, particularly in black and female patients.
doi:10.1200/JCO.2010.31.7255
PMCID: PMC3082978  PMID: 21422438
18.  Vitamin D and Its Role During Pregnancy in Attaining Optimal Health of Mother and Fetus 
Nutrients  2012;4(3):208-230.
Despite its discovery a hundred years ago, vitamin D has emerged as one of the most controversial nutrients and prohormones of the 21st century. Its role in calcium metabolism and bone health is undisputed but its role in immune function and long-term health is debated. There are clear indicators from in vitro and animal in vivo studies that point to vitamin D’s indisputable role in both innate and adaptive immunity; however, the translation of these findings to clinical practice, including the care of the pregnant woman, has not occurred. Until recently, there has been a paucity of data from randomized controlled trials to establish clear cut beneficial effects of vitamin D supplementation during pregnancy. An overview of vitamin metabolism, states of deficiency, and the results of recent clinical trials conducted in the U.S. are presented with an emphasis on what is known and what questions remain to be answered.
doi:10.3390/nu4030208
PMCID: PMC3347028  PMID: 22666547
vitamin D; cholecalciferol; calcitriol; pregnancy; neonate
19.  Plasma 25-OH-Vitamin D Levels in Early Onset, Severe Preeclampsia 
OBJECTIVE
Vitamin D deficiency has been linked to adverse pregnancy outcomes. The purpose of this investigation was to assess total 25-hydroxyvitamin D (25-OH-D) levels at diagnosis of early-onset severe preeclampsia (EOSPE).
STUDY DESIGN
Following IRB approval, subjects with EOSPE (< 34 weeks gestation with severe preeclampsia) were enrolled in this case-control investigation in a 1:2 ratio with gestation matched, contemporaneous controls. Demographic and outcome information was collected for each subject. Plasma total 25-OH-D levels were determined by radioimmunoassay and reported in ng/mL. Results were analyzed by Mann-Whitney U and multivariable regression.
RESULTS
Subjects with EOSPE (n=50) were noted to have decreased total 25-OH-D levels relative to healthy controls (n=100; p<0.001). This difference in total 25-OH-D remained significant after controlling for potential confounders.
CONCLUSION
Total 25-OH-D is decreased at diagnosis of EOSPE. Further study is needed to understand the impact of vitamin D deficiency on pregnancy outcomes.
doi:10.1016/j.ajog.2010.06.036
PMCID: PMC3192365  PMID: 20692641
25-hydroxyvitamin D; adverse pregnancy outcome; preeclampsia; Vitamin D
20.  Blood vitamin D levels in relation to genetic estimation of African ancestry 
Background
African Americans generally have lower circulating levels of 25 hydroxyvitamin D (25(OH)D) than whites, attributed to skin pigmentation and dietary habits. Little is known about the genetic determinants of 25(OH)D levels, nor whether the degree of African ancestry associates with circulating 25(OH)D.
Methods
Using a panel of 276 ancestry informative genetic markers, we estimated African and European admixture for a sample of 758 African American and non-Hispanic white Southern Community Cohort Study participants. For African Americans, cutpoints of <85%, 85%–95%, and ≥95% defined “low”, “medium”, and “high” African ancestry. We estimated the association between African ancestry and 25(OH)D, and also explored whether vitamin D exposure (sunlight, diet) had varying effects on 25(OH)D levels dependent on ancestry level.
Results
Mean serum 25(OH)D levels among whites and among African Americans of low, medium, and high African ancestry were 27.2, 19.5, 18.3, and 16.5ng/mL, respectively. Serum 25(OH)D was estimated to decrease by 1.0–1.1ng/mL per 10% increase in African ancestry. The effect of high vitamin D exposure from sunlight and diet was 46% lower among African Americans with high African ancestry than among those with low/medium ancestry.
Conclusions
We found novel evidence that the level of African ancestry may play a role in clinical vitamin D status.
Impact
This is the first study to describe how 25(OH)D levels vary in relation to genetic estimation of African ancestry. Further study is warranted to replicate these findings and uncover the potential pathways involved.
doi:10.1158/1055-9965.EPI-10-0482
PMCID: PMC2938736  PMID: 20647395
vitamin D; African Americans; health status disparities; genetics; epidemiology
21.  Serum Vitamin D Levels and Severe Asthma Exacerbations in the Childhood Asthma Management Program Study 
Background
Asthma exacerbations, most often due to respiratory tract infections, are the leading causes of asthma morbidity and comprise a significant proportion of asthma-related costs. Vitamin D status may play a role in preventing asthma exacerbations.
Objectives
To assess the relationship between serum vitamin D levels and subsequent severe asthma exacerbations.
Methods
We measured 25-hydroxyvitamin D (25(OH)D) levels in serum collected from 1,024 mild to moderate persistent asthmatic children at the time of enrollment in a multi-center clinical trial of children randomized to receiving budesonide, nedocromil, or placebo (as-needed beta-agonists), the Childhood Asthma Management Program. Using multivariable modeling we examined the relationship between baseline vitamin D level and the odds of any hospitalization or emergency department (ED) visit over the 4 years of the trial.
Results
35% of all subjects were vitamin D insufficient, as defined by a level ≤ 30 ng/ml 25(OH)D. Mean vitamin D levels were lowest in African-American subjects, and highest in whites. After adjusting for age, sex, BMI, income, and treatment group, insufficient vitamin D status was associated with a higher odds of any hospitalization or ED visit (odds ratio [OR] 1.5 [95% confidence interval [CI]: 1.1 – 1.9] P =0.01).
Conclusion
Vitamin D insufficiency is common in this population of North American children with mild to moderate persistent asthma, and is associated with higher odds of severe exacerbation over a four year period.
doi:10.1016/j.jaci.2010.03.043
PMCID: PMC2902692  PMID: 20538327
Asthma; Vitamin D; inhaled corticosteroids; asthma exacerbations
22.  Plasma 25-hydroxyvitamin D and risk of breast cancer in the Nurses' Health Study II 
Introduction
Experimental evidence indicates vitamin D may play an important role in breast cancer etiology but epidemiologic evidence to date is inconsistent. Vitamin D comes from dietary intake and sun exposure and plasma levels of 25-hydroxyvitamin D (25(OH)D) are considered the best measure of vitamin D status.
Methods
We conducted a prospective nested case-control study within the Nurses' Health Study II (NHSII). Plasma samples collected in 1996 to 1999 were assayed for 25(OH)D in 613 cases, diagnosed after blood collection and before 1 June 2007, and in 1,218 matched controls. Multivariate relative risks (RR) and 95% confidence intervals (CI) were calculated by conditional logistic regression, adjusting for several breast cancer risk factors.
Results
No significant association was observed between plasma 25(OH)D levels and breast cancer risk (top vs. bottom quartile multivariate RR = 1.20, 95% CI (0.88 to 1.63), P-value, test for trend = 0.32). Results were similar when season-specific quartile cut points were used. Results did not change when restricted to women who were premenopausal at blood collection or premenopausal at diagnosis. Results were similar between estrogen receptor (ER)+/progesterone receptor (PR)+ and ER-/PR- tumors (P-value, test for heterogeneity = 0.51). The association did not vary by age at blood collection or season of blood collection, but did vary when stratified by body mass index (P-value, test for heterogeneity = 0.01).
Conclusions
Circulating 25(OH)D levels were not significantly associated with breast cancer risk in this predominantly premenopausal population.
doi:10.1186/bcr2880
PMCID: PMC3218936  PMID: 21569367
23.  Prediagnostic Plasma Vitamin D Metabolites and Mortality among Patients with Prostate Cancer 
PLoS ONE  2011;6(4):e18625.
Background
Laboratory evidence suggests that vitamin D might influence prostate cancer prognosis.
Methodology/Principal Findings
We examined the associations between prediagnostic plasma levels of 25(OH)vitamin D [25(OH)D] and 1,25(OH)2vitamin D [1,25(OH)2D] and mortality among 1822 participants of the Health Professionals Follow-up Study and Physicians' Health Study who were diagnosed with prostate cancer. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total mortality (n = 595) and lethal prostate cancer (death from prostate cancer or development of bone metastases; n = 202). In models adjusted for age at diagnosis, BMI, physical activity, and smoking, we observed a HR of 1.22 (95% CI: 0.97, 1.54) for total mortality, comparing men in the lowest to the highest quartile of 25(OH)D. There was no association between 1,25(OH)2D and total mortality. Men with the lowest 25(OH)D quartile were more likely to die of their cancer (HR: 1.59; 95% CI: 1.06, 2.39) compared to those in the highest quartile (Ptrend = 0.006). This association was largely explained by the association between low 25(OH)D levels and advanced cancer stage and higher Gleason score, suggesting that these variables may mediate the influence of 25(OH)D on prognosis. The association also tended to be stronger among patients with samples collected within five years of cancer diagnosis. 1,25(OH)2D levels were not associated with lethal prostate cancer.
Conclusions/Significance
Although potential bias of less advanced disease due to more screening activity among men with high 25(OH)D levels cannot be ruled out, higher prediagnostic plasma 25(OH)D might be associated with improved prostate cancer prognosis.
doi:10.1371/journal.pone.0018625
PMCID: PMC3071841  PMID: 21494639
24.  Serum Vitamin D and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Screening Trial 
Cancer research  2009;69(4):1439-1447.
Experimental evidence suggests that vitamin D has anti-carcinogenic properties; however, a nested case-control study conducted in a population of male Finnish smokers found that higher 25-hydroxyvitamin D [25(OH)D], the best indicator of vitamin D status as determined by the sun and diet, was associated with a significant 3-fold increased risk for pancreatic cancer. We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Screening Trial cohort of men and women 55 to 74 years of age at baseline to test whether prediagnostic serum 25(OH)D concentrations were associated with pancreatic cancer risk. Between 1994 and 2006, 184 incident cases of pancreatic adenocarcinoma occurred (follow-up to 11.7 years). Two controls (n = 368) who were alive at the time the case was diagnosed were selected for each case and matched by age, race, sex, and calendar date of blood draw (to control for seasonal variation). We calculated odds ratios (OR) and 95% confidence intervals (95% CI) using conditional logistic regression, adjusting for smoking and body mass index. Vitamin D concentrations were not associated with pancreatic cancer overall (highest versus lowest quintile, >82.3 versus <45.9 nmol/L: OR, 1.45; 95% CI, 0.66–3.15; P trend = 0.49). However, positive associations were observed among subjects with low estimated annual residential solar UBV exposure, but not among those with moderate to high annual exposure (P interaction = 0.015). We did not confirm the previous strong positive association between 25(OH)D and pancreatic cancer; however, the increased risk among participants with low residential UVB exposure is similar.
doi:10.1158/0008-5472.CAN-08-2694
PMCID: PMC3052200  PMID: 19208842
25.  Serum Vitamin D and Breast Density in Breast Cancer Survivors 
Background:
Vitamin D influences cellular proliferation and proliferation-related breast tissue characteristics, such as mammographic breast density. Little is known about vitamin D status, assessed by serum [25(OH)D], and its relationship to breast density in breast cancer survivors.
Methods:
Participants were 426 postmenopausal breast cancer survivors from the HEAL (Health, Eating, Activity and Lifestyle) Study. Women from New Mexico, Los Angeles and western Washington were enrolled post-diagnosis. Data for this report are from an examination conducted 24 months post-enrollment. Participants completed health-related questionnaires, gave fasting blood samples and completed height and weight measurements. Serum [25(OH)D] was assayed by radioimmunoabsorbant (RIA) assay. Breast dense area and percent density were measured from post-diagnosis digitized mammograms. Multivariate linear regression tested associations of serum [25(OH)D] with mammographic breast density measures.
Results:
Of the 426 participants, 22.8% were African-American, 11.3% were Hispanic and 62.8% were non-Hispanic white. We observed no associations of serum [25(OH)D] with either breast density or breast dense area. Among women with vitamin D deficiency (serum [25(OH)D] <16.0 ng/ml) (n=103), mean percent breast density was 8.0% and among those with sufficient status (n=99) (serum [25(OH)D] ≥ 32.0 ng/ml) mean percent density was 8.5%. Breast dense area averaged 27.2 and 26.2 cm2 for women with vitamin D deficiency and sufficiency, respectively.
Conclusion:
Data from this multiethnic cohort of breast cancer survivors do not support the hypothesis that serum vitamin D, [25(OH)D], is associated with breast density in cancer survivors.
doi:10.1158/1055-9965.EPI-09-0774
PMCID: PMC2819627  PMID: 20086111
Vitamin D; mammography; breast cancer

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