Caroline E. Boeke

Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood: prospective results from a folate-replete population.

Maternal diet affects offspring DNA methylation in animal models, but evidence from humans is limited. We investigated the extent to which gestational intake of methyl donor nutrients affects global DNA methylation in maternal and umbilical cord blood. Among mother-infant pairs in Project Viva, a folate-replete US population, we estimated maternal intakes of vitamin B12, betaine, choline, folate, cadmium, zinc and iron periconceptionally and during the second trimester. We examined associations of these nutrients with DNA methylation, measured as %5-methyl cytosines (%5mC) in Long Interspersed Nuclear Element-1 (LINE-1), in first trimester (n = 830) and second trimester (n = 671) maternal blood and in cord blood at delivery (n = 516). Cord blood methylation was higher for male than female infants {mean [standard deviation (SD)] 84.8 [0.6] vs. 84.4 [0.7]%}. In the multivariable-adjusted model, maternal intake of methyl donor nutrients periconceptionally and during the second trimester of pregnancy was not positively associated with first trimester, second trimester or cord blood LINE-1 methylation. Periconceptional betaine intake was inversely associated with cord blood methylation [regression coefficient = -0.08% (95% confidence interval (CI): -0.14,-0.01)] but this association was attenuated after adjustment for dietary cadmium, which itself was directly associated with first trimester methylation and inversely associated with cord blood methylation. We also found an inverse association between periconceptional choline [-0.10%, 95% CI: -0.17,-0.03 for each SD (~63 mg/d)] and cord blood methylation in males only. In this folate-replete population, we did not find positive associations between intake of methyl donor nutrients during pregnancy and DNA methylation overall, but among males, higher early pregnancy intakes of choline were associated with lower cord blood methylation.

Established breast cancer risk factors and risk of intrinsic tumor subtypes.

Breast cancer is a heterogeneous disease with multiple intrinsic tumor subtypes. These subtypes vary in tumor gene expression and phenotype, and are most commonly grouped into four major subtypes: luminal A, luminal B, HER2-overexpressing and triple negative (or basal-like). A growing number of studies have evaluated the relationship between established breast cancer risk factors and risk of one or more intrinsic tumor subtypes. We conducted a systematic review of 38 studies to synthesize their results and identify areas requiring more research. Taken together, published studies suggest that most established breast cancer risk factors reflect risk factors for the luminal A subtype of breast cancer, and some breast cancer risk factors may be differentially associated with other intrinsic tumor subtypes. Future breast cancer research will need to consider etiologic differences across subtypes and design studies focused on understanding the etiology and prevention of less common tumor subtypes.

Correlations among adiposity measures in school-aged children

BackgroundGiven that it is not feasible to use dual x-ray absorptiometry (DXA) or other reference methods to measure adiposity in all pediatric clinical and research settings, it is important to identify reasonable alternatives. Therefore, we sought to determine the extent to which other adiposity measures were correlated with DXA fat mass in school-aged children.MethodsIn 1110 children aged 6.5-10.9 years in the pre-birth cohort Project Viva, we calculated Spearman correlation coefficients between DXA (n=875) and other adiposity measures including body mass index (BMI), skinfold thickness, circumferences, and bioimpedance. We also computed correlations between lean body mass measures.Results50.0% of the children were female and 36.5% were non-white. Mean (SD) BMI was 17.2 (3.1) and total fat mass by DXA was 7.5 (3.9) kg. DXA total fat mass was highly correlated with BMI (rs=0.83), bioimpedance total fat (rs=0.87), and sum of skinfolds (rs=0.90), and DXA trunk fat was highly correlated with waist circumference (rs=0.79). Correlations of BMI with other adiposity indices were high, e.g., with waist circumference (rs=0.86) and sum of subscapular plus triceps skinfolds (rs=0.79). DXA fat-free mass and bioimpedance fat-free mass were highly correlated (rs=0.94).ConclusionsIn school-aged children, BMI, sum of skinfolds, and other adiposity measures were strongly correlated with DXA fat mass. Although these measurement methods have limitations, BMI and skinfolds are adequate surrogate measures of relative adiposity in children when DXA is not practical.

Choline Intake During Pregnancy and Child Cognition at Age 7 Years

Animal models indicate that exposure to choline in utero improves visual memory through cholinergic transmission and/or epigenetic mechanisms. Among 895 mothers in Project Viva (eastern Massachusetts, 1999-2002 to 2008-2011), we estimated the associations between intakes of choline, vitamin B12, betaine, and folate during the first and second trimesters of pregnancy and offspring visual memory (measured by the Wide Range Assessment of Memory and Learning, Second Edition (WRAML2), Design and Picture Memory subtests) and intelligence (measured using the Kaufman Brief Intelligence Test, Second Edition (KBIT-2)) at age 7 years. Mean second-trimester intakes were 328 (standard deviation (SD), 63) mg/day for choline, 10.5 (SD, 5.1) µg/day for vitamin B12, 240 (SD, 104) mg/day for betaine, and 1,268 (SD, 381) µg/day for folate. Mean age 7 test scores were 17.2 (SD, 4.4) points on the WRAML 2 Design and Picture Memory subtests, 114.3 (SD, 13.9) points on the verbal KBIT-2, and 107.8 (SD, 16.5) points on the nonverbal KBIT-2. In a model adjusting for maternal characteristics, the other nutrients, and childs age and sex, the top quartile of second-trimester choline intake was associated with a child WRAML2 score 1.4 points higher (95% confidence interval: 0.5, 2.4) than the bottom quartile (P-trend = 0.003). Results for first-trimester intake were in the same direction but weaker. Intake of the other nutrients was not associated with the cognitive tests administered. Higher gestational choline intake was associated with modestly better child visual memory at age 7 years.

Differential Associations of Leptin with Adiposity Across Early Childhood

To examine associations of perinatal and 3‐year leptin with weight gain and adiposity through 7 years.

Associations of LINE-1 DNA Methylation with Preterm Birth in a Prospective Cohort Study

Preterm birth affects over 12% of all infants born in the US yet the biology of early delivery remains unclear, including whether epigenetic mechanisms are involved. We examined associations of maternal and umbilical cord blood long interspersed nuclear element-1 (LINE-1) DNA methylation with length of gestation and odds of preterm birth in singleton pregnancies in Project Viva. In white blood cells from maternal blood during 1(st) trimester (n=914) and 2(nd) trimester (n=922), and from venous cord blood at delivery (n=557), we measured LINE-1 by pyrosequencing (expressed as %5 methyl cytosines within the LINE-1 region analyzed [%5mC]). We ran linear regression models to analyze differences in gestation length, and logistic models for odds of preterm birth (<37 v. ≥37 weeks gestation), across quartiles of LINE-1. Mean(SD) LINE-1 levels were 84.3(0.6), 84.5(0.4), and 84.6(0.7) %5mC for 1(st) trimester, 2(nd) trimester and cord blood, respectively. Mean(SD) gestational age was 39.5(1.8) weeks, and 6.5% of infants were born preterm. After adjustment for maternal age, race/ethnicity, BMI, education, smoking status, and fetal sex, women with the highest vs. lowest quartile of 1(st) trimester LINE-1 had longer gestations (0.45 weeks [95% CI 0.12, 0.78]) and lower odds of preterm birth (OR 0.40 [0.17, 0.94]), whereas associations with cord blood LINE-1 were in the opposite direction (-0.45 weeks, -0.83, -0.08) and (OR 4.55 [1.18, 17.5]). In conclusion, higher early pregnancy LINE-1 predicts lower risk of preterm birth. In contrast, preterm birth is associated with lower LINE-1 in cord blood.

Intestinal Protozoan Infections in Relation to Nutritional Status and Gastrointestinal Morbidity in Colombian School Children

While Giardia duodenalis infection has been consistently associated with nutrient malabsorption and stunting in children, the effects of other protozoans on nutritional status or gastrointestinal morbidity are less clear. We sought to determine whether infection with common intestinal protozoans including Giardia duodenalis, Entamoeba coli and Blastocystis hominis was associated with anthropometric and micronutrient status, gastrointestinal symptoms, visits to the doctor or school absenteeism in children 5-12 years of age from Bogotá, Colombia. We obtained stool samples from 442 children enrolled in primary schools in 2006 and examined the presence of intestinal protozoans in relation to height, body mass index, plasma concentrations of vitamins A and B12, ferritin and zinc and erythrocyte folate. In addition, we examined the associations between protozoan infections and the incidence of common gastrointestinal symptoms, which were registered prospectively in morbidity diaries. The prevalence rates of G. duodenalis, E. coli and B. hominis infection were 6.3, 23.1 and 22.4%, respectively. Giardia infection was associated with lower height-for-age z-score (p = 0.04), whereas E. coli infection was associated with low erythrocyte folate (p = 0.04), and B. hominis infection was related to higher vitamin A levels (p = 0.05). Infection with E. coli was also associated with a significantly higher incidence of fever but fewer visits to the doctor, while B. hominis infection was associated with significantly less diarrhea, diarrhea with vomiting, doctor visits and school absenteeism. In conclusion, G. duodenalis and E. coli infections were associated with indicators of poor nutritional status in this population, while B. hominis was related to apparently decreased morbidity.

Childhood sleep duration and quality in relation to leptin concentration in two cohort studies.

STUDY OBJECTIVES Poor sleep in childhood is associated with increased obesity risk, possibly by affecting appetite-regulating hormones such as leptin. We examined short- and long-term sleep duration and quality in relation to leptin in two US pediatric cohorts. DESIGN Analysis of data from two prospective cohort studies. SETTING Population-based. Adolescent polysomnography assessments performed in a clinical research unit. PATIENTS OR PARTICIPANTS Children in Project Viva (n = 655) and adolescents in the Cleveland Childrens Sleep & Health Study (n = 502). INTERVENTIONS N/A. MEASUREMENTS AND RESULTS In Project Viva, mothers reported average child sleep duration annually from infancy through age 7, and we measured leptin at ages 3 and 7. In the Cleveland Childrens Sleep & Health Study, we collected self-reported sleep duration, polysomnography-derived measures of sleep quality, and fasting leptin at ages 16-19. In sex-stratified linear regression analyses adjusted for sociodemographic characteristics and adiposity, chronic curtailed sleep was associated with lower leptin at age 7 in girls; a one-unit decrease in sleep score was associated with a 0.08 decrease in log leptin (95% CI: 0.01,0.15). The association was stronger in girls with greater adiposity (P = 0.01). Among adolescents, shorter sleep was associated with lower leptin in males; each one-hour decrease in sleep duration was associated with a 0.06 decrease in log leptin (95% CI: 0.00, 0.11). Sleep duration was not associated with leptin at other ages. Sleep quality indices were not associated with leptin. CONCLUSIONS Our results suggest possible age-specific sexual dimorphism in the influence of sleep on leptin, which may partly explain inconsistencies in the literature.

Adolescent Carotenoid Intake and Benign Breast Disease

BACKGROUND: Carotenoids may reduce risk of benign breast disease (BBD), an independent risk factor for breast cancer, through antioxidative or antiproliferative mechanisms. Exposure to carotenoids may be most important during adolescence when breast tissue is still developing. We examined adolescent carotenoid intake in relation to BBD in young women. METHODS: In 6593 adolescent girls in the prospective Growing Up Today Study cohort, intakes of α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, and lycopene were assessed by using the means from food-frequency questionnaires in 1996, 1997, and 1998. Girls reported biopsy-confirmed BBD on questionnaires in 2005, 2007, and 2010 (n = 122). We conducted logistic regression of energy-adjusted carotenoid intakes in relation to BBD, adjusted for age, family history of breast cancer or BBD, age at menarche, nulliparity, alcohol intake, BMI, and physical activity. RESULTS: Mean (SD) age at baseline was 12.0 (1.6) years. β-Carotene intake was inversely associated with BBD; comparing the highest to lowest quartile, the multivariate-adjusted odds ratio was 0.58 (95% confidence interval: 0.34–1.00; P-trend = .03). α-Carotene and lutein/zeaxanthin were also inversely associated with BBD, but the associations were not statistically significant. CONCLUSIONS: Adolescent carotenoid intake may be associated with lower BBD risk; these findings warrant further study.

Triggers of spontaneous preterm delivery--why today?

BACKGROUND Our goal is to study the triggers of spontaneous preterm delivery using a case-crossover design. METHODS In a pilot study, we enrolled 50 women with spontaneous preterm labour (PTL) and 50 with preterm premature rupture of membranes (PPROM) between 2011 and 2012. To assess non-transient risk factors, we also enrolled a control group of 158 pregnant women at their regular prenatal care visits matched to cases by gestational age and calendar time. The index time was defined as the onset of PTL/PPROM (for cases) or interview (for controls). Detailed data were collected through structured interviews regarding factors of interest during the 72 h that preceded the index time. Within case subjects, we compared the frequency of transient factors from 0 to 24 h before index time with that from 48 to 72 h before index time, and estimated matched odds ratios (OR) and 95% confidence intervals (CI). RESULTS Previously hypothesised chronic risk factors for spontaneous preterm delivery, including mood disorders and stressful events, were more common among cases than among controls. Within cases, skipped meals [OR 4.3, 95% CI 1.2, 15.2], disturbed sleep [OR 4.5, 95% CI 1.5, 13.3], sexual activity [OR 6.0, 95% CI 0.7, 69.8], and intake of spicy foods [OR 7.0, 95% CI 1.6, 30.8] were associated with an increased risk for PTL/PPROM within the subsequent 24 h. For physical exertion and other potential risk factors evaluated, the OR was close to the null. CONCLUSION Skipping meals and disturbed sleep may be associated with imminent PTL/PPROM; sexual activity and spicy food may trigger PTL/PPROM in susceptible women. Larger case-crossover studies will be able to evaluate the impact of modifiable risk factors and acute predictors of PTL/PPROM, and might help guide obstetrical management.