Camille E. Powe

Vitamin D–Binding Protein and Vitamin D Status of Black Americans and White Americans

BACKGROUND Low levels of total 25-hydroxyvitamin D are common among black Americans. Vitamin D-binding protein has not been considered in the assessment of vitamin D deficiency. METHODS In the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of blacks and whites (2085 participants), we measured levels of total 25-hydroxyvitamin D, vitamin D-binding protein, and parathyroid hormone as well as bone mineral density (BMD). We genotyped study participants for two common polymorphisms in the vitamin D-binding protein gene (rs7041 and rs4588). We estimated levels of bioavailable 25-hydroxyvitamin D in homozygous participants. RESULTS Mean (±SE) levels of both total 25-hydroxyvitamin D and vitamin D-binding protein were lower in blacks than in whites (total 25-hydroxyvitamin D, 15.6±0.2 ng per milliliter vs. 25.8±0.4 ng per milliliter, P<0.001; vitamin D-binding protein, 168±3 μg per milliliter vs. 337±5 μg per milliliter, P<0.001). Genetic polymorphisms independently appeared to explain 79.4% and 9.9% of the variation in levels of vitamin D-binding protein and total 25-hydroxyvitamin D, respectively. BMD was higher in blacks than in whites (1.05±0.01 g per square centimeter vs. 0.94±0.01 g per square centimeter, P<0.001). Levels of parathyroid hormone increased with decreasing levels of total or bioavailable 25-hydroxyvitamin D (P<0.001 for both relationships), yet within each quintile of parathyroid hormone concentration, blacks had significantly lower levels of total 25-hydroxyvitamin D than whites. Among homozygous participants, blacks and whites had similar levels of bioavailable 25-hydroxyvitamin D overall (2.9±0.1 ng per milliliter and 3.1±0.1 ng per milliliter, respectively; P=0.71) and within quintiles of parathyroid hormone concentration. CONCLUSIONS Community-dwelling black Americans, as compared with whites, had low levels of total 25-hydroxyvitamin D and vitamin D-binding protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyvitamin D. Racial differences in the prevalence of common genetic polymorphisms provide a likely explanation for this observation. (Funded by the National Institute on Aging and others.).

Preeclampsia, a Disease of the Maternal Endothelium The Role of Antiangiogenic Factors and Implications for Later Cardiovascular Disease

Preeclampsia is a clinical syndrome defined as the new onset of hypertension and proteinuria during the second half of pregnancy.1 It afflicts 3% to 5% of pregnancies and is a leading cause of maternal mortality, especially in developing countries.2,3 Because the only known remedy is delivery of the placenta, in developed countries preeclampsia is an important cause of premature delivery, usually medically indicated for the benefit of the mother. This results in infant morbidity and substantial healthcare expenditure.4 Despite the considerable morbidity and mortality, the cause of preeclampsia has remained enigmatic. Both hypertension and proteinuria implicate the endothelium as the target of the disease. The hypertension of preeclampsia is characterized by peripheral vasoconstriction and decreased arterial compliance.5,6 The proteinuria of preeclampsia is associated with a pathognomonic renal lesion known as glomerular endotheliosis, in which the endothelial cells of the glomerulus swell and endothelial fenestrations are lost.7,8 Podocyturia has been recently associated with preeclampsia during clinical disease9; however, whether this is the cause or effect of proteinuria is unknown. The glomerular filtration rate is decreased compared with normotensive pregnant women; in rare cases, acute renal failure may develop. Preeclampsia is a systemic vascular disorder that may also affect the liver and the brain in the mothers. When the liver is involved, women may present with abdominal pain, nausea, vomiting, and elevated liver enzymes. Pathological examination of the liver reveals periportal and sinusoidal fibrin deposition and, in more extreme cases, hemorrhage and necrosis.10 The severe preeclampsia variant HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurs in ≈20% of women with severe preeclampsia,11 and is named not only for the liver involvement, but also for the disorder of the coagulation system that develops.12 Approximately 20% of …

Angiogenic Factors and the Risk of Adverse Outcomes in Women with Suspected Preeclampsia

Background— An imbalance in circulating angiogenic factors plays a central role in the pathogenesis of preeclampsia. Methods and Results— We prospectively studied 616 women who were evaluated for suspected preeclampsia. We measured plasma levels of antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) at presentation and examined for an association between the sFlt1/PlGF ratio and subsequent adverse maternal and perinatal outcomes within 2 weeks. The median sFlt1/PlGF ratio at presentation was elevated in participants who experienced any adverse outcome compared with those who did not (47.0 [25th–75th percentile, 15.5–112.2] versus 10.8 [25th–75th percentile, 4.1–28.6]; P<0.0001). Among those presenting at <34 weeks (n=167), the results were more striking (226.6 [25th–75th percentile, 50.4–547.3] versus 4.5 [25th–75th percentile, 2.0–13.5]; P<0.0001), and the risk was markedly elevated when the highest sFlt1/PlGF ratio tertile was compared with the lowest (odds ratio, 47.8; 95% confidence interval, 14.6–156.6). Among participants presenting at <34 weeks, the addition of sFlt1/PlGF ratio to hypertension and proteinuria significantly improved the prediction for subsequent adverse outcomes (area under the curve, 0.93 for hypertension, proteinuria, and sFlt1/PlGF versus 0.84 for hypertension and proteinuria alone; P=0.001). Delivery occurred within 2 weeks of presentation in 86.0% of women with an sFlt1/PlGF ratio ≥85 compared with 15.8% of women with an sFlt1/PlGF ratio <85 (hazard ratio, 15.2; 95% confidence interval, 8.0–28.7). Conclusions— In women with suspected preeclampsia presenting at <34 weeks, circulating sFlt1/PlGF ratio predicts adverse outcomes occurring within 2 weeks. The accuracy of this test is substantially better than that of current approaches and may be useful in risk stratification and management. Additional studies are warranted to validate these findings.

Vitamin D–binding protein modifies the vitamin D–bone mineral density relationship

Studies examining the relationship between total circulating 25‐hydroxyvitamin D [25(OH)D] levels and bone mineral density (BMD) have yielded mixed results. Vitamin D–binding protein (DBP), the major carrier protein for 25(OH)D, may alter the biologic activity of circulating vitamin D. We hypothesized that free and bioavailable 25(OH)D, calculated from total 25(OH)D, DBP, and serum albumin levels, would be more strongly associated with BMD than levels of total 25(OH)D. We measured total 25(OH)D, DBP, and serum albumin levels in 49 healthy young adults enrolled in the Metabolic Abnormalities in College‐Aged Students (MACS) study. Lumbar spine BMD was measured in all subjects using dual‐energy X‐ray absorptiometry. Clinical, diet, and laboratory information also was gathered at this time. We determined free and bioavailable (free + albumin‐bound) 25(OH)D using previously validated formulas and examined their associations with BMD. BMD was not associated with total 25(OH)D levels (r = 0.172, p = .236). In contrast, free and bioavailable 25(OH)D levels were positively correlated with BMD (r = 0.413, p = .003 for free, r = 0.441, p = .002 for bioavailable). Bioavailable 25(OH)D levels remained independently associated with BMD in multivariate regression models adjusting for age, sex, body mass index, and race (p = .03). It is concluded that free and bioavailable 25(OH)D are more strongly correlated with BMD than total 25(OH)D. These findings have important implications for vitamin D supplementation in vitamin D–deficient states. Future studies should continue to explore the relationship between free and bioavailable 25(OH)D and health outcomes.

Bioavailable Vitamin D Is More Tightly Linked to Mineral Metabolism than Total Vitamin D in Incident Hemodialysis Patients

Prior studies showed conflicting results regarding the association between 25-hydroxyvitamin D (25(OH)D) levels and mineral metabolism in end-stage renal disease. In order to determine whether the bioavailable vitamin D (that fraction not bound to vitamin D binding protein) associates more strongly with measures of mineral metabolism than total levels, we identified 94 patients with previously measured 25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)2D) from a cohort of incident hemodialysis patients. Vitamin D binding protein was measured from stored serum samples. Bioavailable 25(OH)D and 1,25(OH)2D were determined using previously validated formulae. Associations with demographic factors and measures of mineral metabolism were examined. When compared with whites, black patients had lower levels of total, but not bioavailable, 25(OH)D. Bioavailable, but not total, 25(OH)D and 1,25(OH)2D were each significantly correlated with serum calcium. In univariate and multivariate regression analysis, only bioavailable 25(OH)D was significantly associated with parathyroid hormone levels. Hence, bioavailable vitamin D levels are better correlated with measures of mineral metabolism than total levels in patients on hemodialysis.

First Trimester Vitamin D, Vitamin D Binding Protein, and Subsequent Preeclampsia

Previous studies report an association between vitamin D deficiency and hypertension, including the pregnancy-specific disorder preeclampsia. Circulating vitamin D is almost entirely bound to vitamin D binding protein, which increases 2-fold during pregnancy and previous studies have not examined vitamin D binding protein or free vitamin D levels. We performed a nested case-control study within the Massachusetts General Hospital Obstetric Maternal Study, measuring first trimester total 25-hydroxyvitamin D (25[OH]D) and vitamin D binding protein and calculating free 25(OH)D levels. We compared these levels from pregnancies complicated by subsequent preeclampsia (cases, n=39) with those from normotensive pregnancies (controls, n=131). First trimester total 25(OH)D levels were similar in cases and controls (27.4±1.9 versus 28.8±0.80 ng/mL; P=0.435). Despite an association between higher first trimester blood pressures and subsequent preeclampsia, first trimester total 25(OH)D was not associated with first trimester systolic (r=0.11; P=0.16) or diastolic blood pressures (r=0.03; P=0.72). Although there was a trend toward increased risk of preeclampsia with 25(OH)D levels <15 ng/mL (odds ratio: 2.5 [95% CI: 0.89 to 6.90]), this was attenuated after adjustment for body mass index and other covariates (odds ratio: 1.35 [95% CI: 0.40 to 4.50]). First trimester vitamin D binding protein and free 25(OH)D levels were similar in cases and controls and were not associated with first trimester blood pressures. These data suggest that first trimester total and free 25(OH)D levels are not independently associated with first trimester blood pressure or subsequent preeclampsia.

Infant sex predicts breast milk energy content.

During human evolutionary history, and for many around the world, breast milk is the primary source of nutritional energy for infants. Variation in breast milk quality might logically have important effects on infant health, growth, and development, yet the sources of this variation remain largely unelucidated. We quantified nutrient and energy content of breast milk from 25 healthy, well‐nourished Massachusetts mothers with infants aged 2–5 months. We examined several potential sources of variation in milk quality, particularly feeding patterns, infant sex, and maternal breast growth during pregnancy. After controlling for time since last feeding, a known correlate of milk composition, we found that mothers of male infants produced milk that had 25% greater energy content than mothers of female infants (P < 0.001). Change in maternal bra cup size during pregnancy was associated with 16.17 kcal/100 ml greater energy content of milk (P = 0.009), but was not significant after taking infant sex into account. Greater nutritional investment in sons may account for the greater observed growth rates in male compared to female infants. Am. J. Hum. Biol. 2010.

Clinical characterization and outcomes of preeclampsia with normal angiogenic profile

Objective: To compare the clinical characteristics and outcomes of preeclamptic women presenting with a normal plasma angiogenic profile with those subjects who are characterized by an abnormal angiogenic profile. Methods: This was a secondary analysis of a prospective cohort study in women presenting to obstetrical triage at <37 weeks of gestation and diagnosed with preeclampsia within 2 weeks of enrollment and in whom angiogenic factors (sFlt1 and PlGF) measurements were available. Patients were divided into two groups based on their circulating levels of these factors described as a ratio; the sFlt1/PlGF ratio, non-angiogenic preeclampsia (sFlt1/PlGF ratio <85) and angiogenic preeclampsia (sFlt1/PlGF ratio ≥85). The data are presented by sFlt1/PlGF category using median and quartile 1–quartile 3 for continuous variables and by frequency and sample sizes for categorical variables. Results: In our cohort, the patients with non-angiogenic preeclampsia (N = 46) were more obese [BMI: 35.2 (31.6, 38.7) versus 31.1 (28.0, 39.0), p = 0.04], more likely to have preexisting diabetes (21.7% versus 2.0%, p = 0.002) and presented at a later gestational age [35 (32, 37) versus 32 (29, 34) weeks, p < 0.0001] as compared with women with angiogenic preeclampsia (N = 51). Women with non-angiogenic preeclampsia had no serious adverse outcomes (elevated liver function tests/low platelets: 0% versus 23.5%, abruption: 0% versus 9.8%, pulmonary edema: 0% versus 3.9%, eclampsia: 0% versus 2.0 %, small for gestational age: 0% versus 17.7% and fetal/neonatal death: 0% versus 5.9%) as compared with women with angiogenic preeclampsia. The rate of preterm delivery <34 weeks was 8.7% in non-angiogenic preeclampsia compared with 64.7% in angiogenic preeclampsia (p < 0.0001). Interestingly, delivery between 34 and 37 weeks and resource utilization (hospital admission days) were similar in the two groups. Conclusion: In contrast to the angiogenic form, the non-angiogenic form of preeclampsia is characterized by little to no risk of preeclampsia-related adverse outcomes, other than iatrogenic prematurity. Incorporation of angiogenic biomarkers in the evaluation of preeclampsia may allow accurate and early identification of severe disease.

Genetic Variation in APOL1 Associates with Younger Age at Hemodialysis Initiation

African Americans have a markedly higher incidence of ESRD compared with other racial groups. Two variants in the APOL1 gene, to date observed only among individuals of recent African ancestry, associate with increased risk for renal disease among African Americans. Here, we investigated whether these risk alleles also associate with age at initiation of chronic hemodialysis. We performed a cross-sectional study of 407 nondiabetic African Americans with ESRD who participated in the Accelerated Mortality on Renal Replacement (ArMORR) study, a prospective cohort of incident chronic hemodialysis patients. African Americans carrying two copies of the G1 risk allele initiated chronic hemodialysis at a mean age of 49.0 ± 14.9 years, which was significantly younger than both subjects with one copy of the G1 allele (55.9 ± 16.7 years; P = 0.014) and subjects without either risk allele (61.8 ± 17.1 years; P = 6.2 × 10(-7)). The association between the presence of the G1 allele and age at initiation of hemodialysis remained statistically significant after adjusting for sociodemographic and other potential confounders. We did not detect an association between the G2 risk allele and age at initiation of hemodialysis, but the sample size was limited. In conclusion, genetic variations in APOL1 identify African Americans that initiate chronic hemodialysis at a younger age. Early interventions to prevent progression of kidney disease may benefit this high-risk population.

Vitamin D-binding protein and vitamin D in blacks and whites.

To the Editor: Current assays for vitamin D sufficiency measure total circulating 25-hydroxyvitamin D. However, Powe et al. (Nov. 21 issue)1 conclude that measurement of 25-hydroxyvitamin D that is not bound to the vitamin D–binding protein, which they refer to as bioavailable 25-hydroxyvitamin D, provides a better assessment of sufficiency. They report that the correlation between levels of bioavailable 25-hydroxyvitamin D and levels of parathyroid hormone is stronger than the correlation between levels of total circulating 25-hydroxyvitamin D and levels of parathyroid hormone when evaluated across races. However, they fail to reconcile their findings and the rationale underlying their conclusion with a critical role of the complex of 25-hydroxyvitamin D and vitamin D–binding protein. This complex is taken up by renal proximal tubule epithelial cells through receptor-mediated endocytosis. The 25-hydroxyvitamin D component of the endocytosed complex then becomes the major precursor for circulating 1,25-dihydroxyvitamin D, the active steroid hormone form of vitamin D that is important in the regulation of parathyroid hormone levels.2,3 Thus, in the regulation of parathyroid hormone, the “bioavailable” form of 25-hydroxyvitamin D is, in fact, the form that is bound to the vitamin D–binding protein. Steven J. Weintraub, M.D.