Paulette D. Chandler

Effect of Vitamin D Supplementation on Blood Pressure in Blacks

Blacks have significantly higher rates of hypertension than whites, and lower circulating levels of 25-hydroxyvitamin D. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on blood pressure in blacks. During 2 winters from 2008 to 2010, 283 blacks (median age, 51 years) were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 international units of cholecalciferol per day. At baseline, 3 months, and 6 months, systolic and diastolic pressure and 25-hydroxyvitamin D were measured. The 3-month follow-up was completed in 250 (88%) participants. The difference in systolic pressure between baseline and 3 months was +1.7 mm Hg for those receiving placebo, −0.66 mm Hg for 1000 U/d, −3.4 mm Hg for 2000 U/d, and −4.0 mm Hg for 4000 U/d of cholecalciferol (−1.4 mm Hg for each additional 1000 U/d of cholecalciferol; P=0.04). For each 1-ng/mL increase in plasma 25-hydroxyvitamin D, there was a significant 0.2-mm Hg reduction in systolic pressure (P=0.02). There was no effect of cholecalciferol supplementation on diastolic pressure (P=0.37). Within an unselected population of blacks, 3 months of oral vitamin D3 supplementation significantly, yet modestly, lowered systolic pressure. Future trials of vitamin D supplementation on blood pressure are needed to confirm these promising results, particularly among blacks, a population for whom vitamin D deficiency may play a more specific mechanistic role in the pathogenesis of hypertension.

Effect of Vitamin D Supplementation on Blood Pressure in BlacksNovelty and Significance

Blacks have significantly higher rates of hypertension than whites, and lower circulating levels of 25-hydroxyvitamin D. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on blood pressure in blacks. During 2 winters from 2008 to 2010, 283 blacks (median age, 51 years) were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 international units of cholecalciferol per day. At baseline, 3 months, and 6 months, systolic and diastolic pressure and 25-hydroxyvitamin D were measured. The 3-month follow-up was completed in 250 (88%) participants. The difference in systolic pressure between baseline and 3 months was +1.7 mm Hg for those receiving placebo, −0.66 mm Hg for 1000 U/d, −3.4 mm Hg for 2000 U/d, and −4.0 mm Hg for 4000 U/d of cholecalciferol (−1.4 mm Hg for each additional 1000 U/d of cholecalciferol; P=0.04). For each 1-ng/mL increase in plasma 25-hydroxyvitamin D, there was a significant 0.2-mm Hg reduction in systolic pressure (P=0.02). There was no effect of cholecalciferol supplementation on diastolic pressure (P=0.37). Within an unselected population of blacks, 3 months of oral vitamin D3 supplementation significantly, yet modestly, lowered systolic pressure. Future trials of vitamin D supplementation on blood pressure are needed to confirm these promising results, particularly among blacks, a population for whom vitamin D deficiency may play a more specific mechanistic role in the pathogenesis of hypertension.

Dose response to vitamin D supplementation in African Americans: results of a 4-arm, randomized, placebo-controlled trial

BACKGROUND Association studies have suggested that lower circulating 25-hydroxyvitamin D [25(OH)D] in African Americans may partially underlie higher rates of cardiovascular disease and cancer in this population. Nonetheless, the relation between vitamin D supplementation and 25(OH)D concentrations in African Americans remains undefined. OBJECTIVE Our primary objective was to determine the dose-response relation between vitamin D and plasma 25(OH)D. DESIGN A total of 328 African Americans in Boston, MA, were enrolled over 3 winters from 2007 to 2010 and randomly assigned to receive a placebo or 1000, 2000, or 4000 IU vitamin D₃/d for 3 mo. Subjects completed sociodemographic and dietary questionnaires, and plasma samples were drawn at baseline and 3 and 6 mo. RESULTS Median plasma 25(OH)D concentrations at baseline were 15.1, 16.2, 13.9, and 15.7 ng/mL for subjects randomly assigned to receive the placebo or 1000, 2000, or 4000 IU/d, respectively (P = 0.63). The median plasma 25(OH)D concentration at 3 mo differed significantly between supplementation arms at 13.7, 29.7, 34.8, and 45.9 ng/mL, respectively (P < 0.001). An estimated 1640 IU vitamin D₃/d was needed to raise the plasma 25(OH)D concentration to ≥ 20 ng/mL in ≥ 97.5% of participants, whereas a dose of 4000 IU/d was needed to achieve concentrations ≥ 33 ng/mL in ≥ 80% of subjects. No significant hypercalcemia was seen in a subset of participants. CONCLUSIONS Within African Americans, an estimated 1640 IU vitamin D₃/d was required to achieve concentrations of plasma 25(OH)D recommended by the Institute of Medicine, whereas 4000 IU/d was needed to reach concentrations predicted to reduce cancer and cardiovascular disease risk in prospective observational studies. These results may be helpful for informing future trials of disease prevention.

Impact of Vitamin D Supplementation on Inflammatory Markers in African Americans: Results of a Four-Arm, Randomized, Placebo-Controlled Trial

African Americans have a disproportionate burden of inflammation-associated chronic diseases such as cancer and lower circulating levels of 25-hydroxyvitamin D [25(OH)D]. The effect of vitamin D3 (cholecalciferol) supplementation on inflammatory markers is uncertain. We conducted a randomized, double-blind, placebo-controlled trial of supplemental oral vitamin D (placebo, 1,000, 2,000, or 4,000 IU/day of vitamin D3 orally for 3 months) in 328 African Americans (median age, 51 years) of public housing communities in Boston, MA, who were enrolled over three consecutive winter periods (2007–2010). Change from 0 to 3 months of plasma levels of 25(OH)D, high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, IL-10, and soluble TNF-α receptor type 2 (sTNF-R2) in 292 (89%) participants were measured. Overall, no statistically significant changes in CRP, IL-6, IL-10, and sTNF-R2 were observed after the vitamin D supplementation period. Baseline CRP was significantly inversely associated with the baseline 25(OH)D level (P < 0.001) in unadjusted and adjusted models. An interaction between baseline 25(OH)D and vitamin D supplementation was observed for outcome change in log CRP (month 3–month 0; P for interaction = 0.04). Within an unselected population of African Americans, short-term exposure to vitamin D supplementation produced no change in circulating inflammatory markers. This study confirms the strong independent association of CRP with 25(OH)D status even after adjusting for body mass index. Future studies of longer supplemental vitamin D3 duration are necessary to examine the complex influence of vitamin D3 on CRP and other chronic inflammatory cytokines for possible reduction of cancer health disparities in African Americans. Cancer Prev Res; 7(2); 218–25. ©2013 AACR.

Effect of vitamin D supplementation alone or with calcium on adiposity measures: a systematic review and meta-analysis of randomized controlled trials

CONTEXT The independent or interactive effects of vitamin D and calcium on adiposity remain inconclusive. OBJECTIVE The objective of this systematic review and meta-analysis was to assess whether vitamin D and calcium supplements cause changes in adiposity. DATA SOURCES MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched for literature published from 1966 to March 2014. STUDY SELECTION A systematic search was conducted for randomized clinical trials with ≥ 50 participants aged ≥ 18 years at baseline who had received at least 12 weeks of treatment. Among the inclusion criteria were supplementation with vitamin D with or without calcium and measurement of adiposity (weight, body mass index [BMI], and/or fat mass). DATA EXTRACTION The primary endpoints assessed were changes in weight, BMI, or fat mass. DATA SYNTHESIS Of 953 trials identified, 26 randomized clinical trials (n = 12, vitamin D alone; n = 10, vitamin D plus calcium versus calcium control; n = 4, vitamin D plus calcium versus placebo) with a total of 42,430 participants (median duration, 12 months) met the inclusion criteria. When compared with placebo, vitamin D supplementation had no significant effect on BMI (weighted mean difference [WMD], -0.06 kg/m(2); 95% confidence interval [95%CI], -0.14 to 0.03), weight (WMD, -0.05 kg; 95%CI, -0.32 to 0.23), or fat mass (WMD, -0.43 kg; 95%CI, -1.69 to 0.84). Likewise, no significant reduction in BMI (WMD, 0.02 kg/m(2); 95%CI, -0.11 to 0.14), weight (WMD, 0.12 kg; 95%CI, -0.24 to 0.49), or fat mass (WMD, 0.12 kg; 95%CI, -0.22 to 0.45) was observed in participants who received vitamin D plus calcium compared with those who received calcium control. CONCLUSIONS Supplementation with vitamin D showed no effect on adiposity measures in adults.

Circulating N-Linked Glycoprotein Acetyls and Longitudinal Mortality Risk

RATIONALE Circulating glycoprotein N-acetyl glucosamine residues have recently been associated with incident cardiovascular disease and diabetes mellitus. OBJECTIVE Using a plasma glycan biosignature (GlycA) to identify circulating N-acetyl glycan groups, we examined the longitudinal association between GlycA and mortality among initially healthy individuals. METHODS AND RESULTS We quantified GlycA by 400 MHz (1)H nuclear magnetic resonance spectroscopy in 27,524 participants in the Womens Health Study (NCT00000479). The primary outcome was all-cause mortality. We replicated the findings in an independent cohort of 12,527 individuals in the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial (NCT00239681). We also undertook secondary examination of cardiovascular disease and cancer mortality in the Womens Health Study. In the Womens Health Study, during 524,515 person-years of follow-up (median, 20.5 years), there were 3523 deaths. Risk factor-adjusted multivariable Cox proportional hazard ratio (95% confidence interval) per SD increment in GlycA for all-cause mortality was significantly increased at 5 years (1.21 [1.06-1.40]) and during maximal follow-up (1.14 [1.09-1.16]). Similar risk for all-cause mortality was observed in the replication cohort (1.33 [1.21-1.45]). In the Womens Health Study, risk of cardiovascular disease mortality was increased at 5 years (1.43 [1.05-1.95]) and during maximal follow-up (1.15 [1.04-1.26]) and of cancer mortality at 5 years (1.23 [1.02-1.47]) and during maximal follow-up (1.08 [1.01-1.16]). Examination of correlations and mortality associations adjusted for high-sensitivity C-reactive protein, fibrinogen, and intercellular adhesion molecule-1, suggested that GlycA reflects summative risk related to multiple pathways of systemic inflammation. CONCLUSIONS Among initially healthy individuals, elevated baseline circulating glycoprotein N-acetyl methyl groups were associated with longitudinal risk of all-cause, cardiovascular, and cancer mortality.

Circulating Vitamin D Levels and Risk of Colorectal Cancer in Women

Observational data on the association between circulating 25(OH)D and colorectal cancer risk are limited in women. To determine whether prediagnostic levels of 25(OH)D were associated with risk of incident colorectal cancer in the Womens Health Study (WHS), we conducted a nested case–control study using 274 colorectal cases and 274 controls. Each case was matched to a control by age, ethnicity, fasting status at the time of blood collection, time of day when blood was drawn, and month of blood draw. Conditional logistic regression was used to estimate the OR and 95% confidence interval (CI) for colorectal cancer by 25(OH)D quartiles. Mean plasma 25(OH)D was lower in cases versus controls (21.9 vs. 23.9 ng/mL, P = 0.01). In multivariable-adjusted logistic regression models, plasma 25(OH)D was significantly and inversely associated with odds of colorectal cancer (quartile 4 [Q4] vs. quartile 1 [Q1]: OR, 0.45; 95% CI, 0.25–0.81; Ptrend 0.02). In addition, we observed a somewhat lower risk of colorectal cancer-related mortality after adjustment for matching variables, randomization treatment and other risk factors (Q4:Q1 OR, 0.40; 95% CI, 0.17–0.97; Ptrend 0.05). In this cohort of healthy women, we found a significant inverse association between prediagnostic 25(OH)D levels and risk of incident colorectal cancer, and a borderline significant inverse association between prediagnostic 25(OH)D levels and colorectal cancer-related mortality. These results support a possible association between plasma 25(OH)D and risk of colorectal cancer in women. Cancer Prev Res; 8(8); 675–82. ©2015 AACR. See related commentary by Demetrius Albanes, p. 657

Lipid biomarkers and long-term risk of cancer in the Women’s Health Study

BACKGROUND Lipid biomarkers, such as HDL-cholesterol concentrations, have been shown to have positive, inverse, and null associations with total, breast, and colorectal cancer risks. Studies of novel lipid biomarkers, such as apolipoprotein A-I (apo A-I) and apolipoprotein B-100 (apo B-100), and cancer risk have been sparse, to our knowledge. OBJECTIVES We evaluated the prospective association of total, breast, colorectal, and lung cancers and cancer mortality with circulating lipid biomarkers in 15,602 female health professionals in the Womens Health Study (aged ≥45 y, free of cardiovascular disease and cancer, and without hormone replacement therapy or lipid-lowering medications at baseline). DESIGN Cox regression models estimated HRs of cancer endpoints (19 y median follow-up) across quartiles 1 (reference) to 4 of each lipid biomarker after adjustment for cancer risk factors. RESULTS Confirmed cases included 2163 incident cancer cases (864 breast, 198 colorectal, and 190 lung cancers) and 647 cancer deaths. Total cancer risk was significantly lower in the highest quartile of apo A-I (adjusted HR: 0.79; 95% CI: 0.70, 0.90; P-trend = 0.0008) and HDL cholesterol (HR: 0.85; 95% CI: 0.75, 0.97; P-trend = 0.01). For site-specific cancers, significant associations included colorectal cancer risk with HDL cholesterol (HR: 0.63; 95% CI; 0.41, 0.98; P-trend = 0.03), triglycerides (HR: 1.86; 95% CI: 1.17, 2.97; P-trend = 0.02), and apo B-100 (HR: 1.60; 95% CI: 1.03, 2.49; P-trend = 0.006) and lung cancer risk with HDL cholesterol (HR: 0.59; 95% CI: 0.38, 0.93; P-trend = 0.01). LDL cholesterol was not significantly associated with risk of total cancer or any site-specific cancers. In time-dependent models that were adjusted for the use of a lipid-lowering medication after baseline, these associations remained. CONCLUSIONS Lipids were associated with total, lung, and colorectal cancer risks in women. Lifestyle interventions for heart-disease prevention, which reduce apo B-100 or raise HDL cholesterol, may be associated with reduced cancer risk. The Womens Health Study was registered at clinicaltrials.gov as NCT00000479.

Null Association Between Vitamin D and PSA Levels Among Black Men in a Vitamin D Supplementation Trial

Background: Black men exhibit a high prevalence of vitamin D deficiency as well as a higher incidence of prostate cancer and higher mortality rates from prostate cancer than Whites. There are few data about the effect of vitamin D3 (cholecalciferol) supplementation on prostate-specific antigen (PSA) in healthy Black men. Methods: During three winters from 2007 to 2010, 105 Black men (median age, 48.9 years) of Boston, MA were randomized into a four-arm, double-blind trial for 3 months of placebo, 1,000, 2,000, or 4,000 U of vitamin D3. At baseline and 3 months, free and total PSA was measured. Results: With vitamin D supplementation, no significant differences in free and total PSA were observed; free PSA, −0.0004 ng/mL (P = 0.94) and total PSA, −0.004 ng/mL (P = 0.92) for each additional 1,000 U/d of vitamin D3. Conclusion: Within an unselected population of healthy Black men without a cancer diagnosis, we found no effect of vitamin D supplementation on free or total PSA. Impact: These findings support prior findings of no change in PSA with vitamin D supplementation and emphasize the need for new methods to assess the influence of vitamin D supplementation on prostate cancer prevention. Cancer Epidemiol Biomarkers Prev; 23(9); 1944–7. ©2014 AACR.

Markers of Inflammation and Incident Breast Cancer Risk in the Women’s Health Study

Chronic inflammation may be a risk factor for the development and progression of breast cancer, yet it is unknown which inflammatory biomarkers and pathways are especially relevant. The present study included 27,071 participants (mean age = 54.5 years) in the Womens Health Study who were free of cancer and cardiovascular disease at enrollment (1992-1995), with baseline measures of 4 inflammatory biomarkers: high-sensitivity C-reactive protein, fibrinogen, N-acetyl side-chains of acute phase proteins, and soluble intercellular adhesion molecule-1. We used Cox proportional hazards regression models to evaluate associations between baseline concentrations of biomarkers and incident breast cancer, and adjusted for baseline and time-varying factors such as age and body mass index. Self-reported invasive breast cancer was confirmed against medical records for 1,497 incident cases (90% postmenopausal). We observed different patterns of risk depending on the inflammatory biomarker. There was a significant direct association between fibrinogen and breast cancer risk (for quintile 5 vs. quintile 1, adjusted hazard ratio = 1.25, 95% confidence interval: 1.03, 1.51; P for trend = 0.01). In contrast, soluble intercellular adhesion molecule-1 was inversely associated with breast cancer (for quintile 5 vs. quintile 1, adjusted hazard ratio = 0.79, 95% confidence interval: 0.66, 0.94; P for trend = 0.02). N-acetyl side-chains of acute phase proteins and high-sensitivity C-reactive protein were not associated with breast cancer. The complex association of chronic inflammation and breast cancer may be considered when formulating anti-inflammatory cancer prevention or intervention strategies.