Jessica C. Kiefte-de Jong

High Circulating Folate and Vitamin B-12 Concentrations in Women During Pregnancy Are Associated with Increased Prevalence of Atopic Dermatitis in Their Offspring

Recent studies suggest that in utero exposure of methyl donors influences programming of the fetal immune system in favor of development of allergic disease. The aim of this study was to assess whether the MTHFR C677T polymorphism, folic acid supplementation, and circulating folate and vitamin B-12 concentrations during pregnancy were associated with wheezing, shortness of breath, and atopic dermatitis in offspring. The study was a population-based birth cohort from fetal life until 48 mo (n = 8742). The use of folic acid supplementation during pregnancy was assessed by questionnaire. Plasma folate and serum vitamin B-12 concentrations and the MTHFR C677T polymorphism were available from blood collected in early pregnancy. Atopic dermatitis, wheezing, and shortness of breath in the offspring were assessed by parental-derived questionnaires at 12, 24, 36, and 48 mo. Maternal folate >16.2 nmol/L and vitamin B-12 >178 pmol/L were positively associated with the development of atopic dermatitis [adjusted OR: 1.18 (95% CI: 1.05-1.33) and adjusted OR: 1.30 (95% CI: 1.06-1.60) for the highest quartiles of folate and vitamin B-12 concentrations, respectively] but not with wheezing and shortness of breath. Maternal MTHFR C677T polymorphism and folic acid supplementation were not associated with wheezing, shortness of breath, and atopic dermatitis. No interactions were found by age, family history of atopy, folic acid supplementation, MTHFR C677T polymorphism, or maternal smoking (P-interaction > 0.10). High folate and vitamin B-12 levels during pregnancy are associated with increased prevalence of atopic dermatitis in the offspring. Potential risks of high folate and vitamin B-12 concentrations on allergic outcomes should be evaluated when discussing mandatory fortification programs.

Meta-Analysis Investigating Associations Between Healthy Diet and Fasting Glucose and Insulin Levels and Modification by Loci Associated With Glucose Homeostasis in Data From 15 Cohorts

Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 U.S. and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = -0.004 mmol/L, 95% confidence interval: -0.005, -0.003) and FI (β = -0.008 ln-pmol/L, 95% confidence interval: -0.009, -0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.

Association between global leukocyte DNA methylation, renal function, carotid intima-media thickness and plasma homocysteine in patients with stage 2–4 chronic kidney disease

BACKGROUND Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease (CVD). Preliminary evidence suggests a role for global DNA hypomethylation in the pathogenesis of atherosclerotic complications in CKD. The aims of this study in patients with stage 2-4 CKD were (1) to assess the association between renal function and DNA methylation, (2) to assess the association between DNA methylation and two markers of atherosclerosis [common carotid intima-media thickness (CCA-IMT)] and brachial artery endothelium-dependent, flow-mediated dilatation (BA-FMD) and (3) to examine the effect of a multi-step treatment strategy on DNA methylation. METHODS In the Anti-Oxidant Therapy In Chronic Renal Insufficiency study (ATIC-study), 93 patients with stage 2-4 CKD were included. In a randomized, double-blind, placebo-controlled design, the treatment group received pravastatin to which vitamin E was added after 6 months and homocysteine-lowering B-vitamin therapy after another 6 months. DNA methylation was assessed using tandem mass spectrometry. CCA-IMT and BA-FMD were assessed using B-mode ultrasonography. RESULTS At baseline, global DNA methylation was not associated with the estimated glomerular filtration rate (P = 0.32) or with CCA-IMT (P = 0.62) or BA-FMD (P = 0.51). No effect of the treatment strategy including B-vitamin on global DNA methylation was found either in the total study group or within separate strata of homocysteine concentration and renal function. CONCLUSION In patients with stage 2-4 CKD, global DNA methylation is not associated with renal function or with CCA-IMT or BA-FMD. A treatment strategy that includes B-vitamins did not alter global DNA methylation in these patients. These data do not support the role of DNA hypomethylation in CKD-associated vascular disease in patients with stage 2-4 CKD.

Dietary Intake, FTO genetic variants, and adiposity: A combined analysis of over 16,000 children and adolescents

The FTO gene harbors variation with the strongest effect on adiposity and obesity risk. Previous data support a role for FTO variation in influencing food intake. We conducted a combined analysis of 16,094 boys and girls aged 1–18 years from 14 studies to examine the following: 1) the association between the FTO rs9939609 variant (or a proxy) and total energy and macronutrient intake; and 2) the interaction between the FTO variant and dietary intake, and the effect on BMI. We found that the BMI-increasing allele (minor allele) of the FTO variant was associated with increased total energy intake (effect per allele = 14.3 kcal/day [95% CI 5.9, 22.7 kcal/day], P = 6.5 × 10−4), but not with protein, carbohydrate, or fat intake. We also found that protein intake modified the association between the FTO variant and BMI (interactive effect per allele = 0.08 SD [0.03, 0.12 SD], P for interaction = 7.2 × 10−4): the association between FTO genotype and BMI was much stronger in individuals with high protein intake (effect per allele = 0.10 SD [0.07, 0.13 SD], P = 8.2 × 10−10) than in those with low intake (effect per allele = 0.04 SD [0.01, 0.07 SD], P = 0.02). Our results suggest that the FTO variant that confers a predisposition to higher BMI is associated with higher total energy intake, and that lower dietary protein intake attenuates the association between FTO genotype and adiposity in children and adolescents.

Correlates of physical activity in 2-year-old toddlers: the generation R study.

OBJECTIVE To describe and identify correlates of objectively measured physical activity and sedentary behavior in 2-year-old toddlers. STUDY DESIGN A total of 347 children participating in a birth cohort study wore a unaxial ActiGraph accelerometer during 1 weekday and 1 weekend day. Information on potential correlates was assessed by parent-reported questionnaires, delivery reports, and regular visits to child health centers. Univariate and multivariable linear regression analyses were conducted to examine the associations between potential correlates and the following physical activity outcomes: percentage of time spent in sedentary behavior, percentage of time spent in moderate-to-vigorous physical activity, and mean counts per minute. RESULTS A high percentage of monitored time was spent in sedentary behavior; 85.6% on weekdays and 84.5% on weekend days. Four correlates were significantly associated with at least 1 physical activity outcome in the multivariable regression models: childs sex, childs age, number of siblings, and season of measurement. The associations of gross motor development with moderate-to-vigorous physical activity and mean counts per minute approached significance. Associations of socioeconomic variables and childs body mass index z-score with physical activity outcomes were not significant. CONCLUSION Two-year-old toddlers spend most of their time in sedentary behavior. No modifiable correlates were identified. Further research on physical activity and associated health benefits among very young children is warranted.

The Development of a Diet Quality Score for Preschool Children and Its Validation and Determinants in the Generation R Study

BACKGROUND Although many studies have examined health effects of infant feeding, studies on diet quality shortly after the weaning and lactation period are scarce. OBJECTIVES Our aims were to develop and evaluate a diet score that measures overall diet quality in preschool children and to examine the sociodemographic and lifestyle determinants of this score. METHODS On the basis of national and international dietary guidelines for young children, we developed a diet score containing 10 components: intake of vegetables; fruit; bread and cereals; rice, pasta, potatoes, and legumes; dairy; meat and eggs; fish; oils and fats; candy and snacks; and sugar-sweetened beverages. The total score ranged from 0 to 10 on a continuous scale and was standardized to an energy intake of 1200 kcal/d with the residual method. The score was evaluated in 3629 children participating in the Generation R Study, a population-based prospective cohort study. Food consumption was assessed with a food-frequency questionnaire (FFQ) at a median age of 13 mo. RESULTS The mean ± SD diet score was 4.1 ± 1.3. The food-based diet score was positively associated with intakes of many nutrients, including n-3 (ω-3) fatty acids [FAs; 0.25 SD increase (95% CI: 0.22, 0.27) per 1 point increase in the diet score], dietary fiber [0.32 (95% CI: 0.30, 0.34)], and calcium [0.13 (95% CI: 0.11, 0.16)], and was inversely associated with intakes of sugars [-0.28 (95% CI: -0.31, -0.26)] and saturated fat [-0.03 (95% CI: -0.05, -0.01)]. A higher diet score was associated with several health-conscious behaviors, such as maternal folic acid supplement use during pregnancy, no smoking during pregnancy, and children watching less television. CONCLUSION We developed a novel food-based diet score for preschool children that could be applied in future studies to compare diet quality in early childhood and to investigate associations between diet in early childhood and growth, health, and development.

The effects of lutein on cardiometabolic health across the life course: a systematic review and meta-analysis

BACKGROUND The antioxidant lutein is suggested as being beneficial to cardiometabolic health because of its protective effect against oxidative stress, but evidence has not systematically been evaluated. OBJECTIVE We aimed to evaluate systematically the effects of lutein (intake or concentrations) on cardiometabolic outcomes in different life stages. DESIGN This is a systematic review with meta-analysis of literature published in MEDLINE, Embase, Cochrane Central, Web of Science, PubMed, and Google Scholar up to August 2014. Included were trials and cohort, case-control, and cross-sectional studies in which the association between lutein concentrations, dietary intake, or supplements and cardiometabolic outcomes was reported. Two independent investigators reviewed the articles. RESULTS Seventy-one relevant articles were identified that included a total of 387,569 participants. Only 1 article investigated the effects of lutein during pregnancy, and 3 studied lutein in children. Furthermore, 31 longitudinal, 33 cross-sectional, and 3 intervention studies were conducted in adults. Meta-analysis showed a lower risk of coronary heart disease (pooled RR: 0.88; 95% CI: 0.80, 0.98) and stroke (pooled RR: 0.82; 95% CI: 0.72, 0.93) for the highest compared with the lowest tertile of lutein blood concentration or intake. There was no significant association with type 2 diabetes mellitus (pooled RR: 0.97; 95% CI: 0.77, 1.22), but higher lutein was associated with a lower risk of metabolic syndrome (pooled RR: 0.75; 95% CI: 0.60, 0.92) for the highest compared with the lowest tertile. The literature on risk factors for cardiometabolic diseases showed that lutein might be beneficial for atherosclerosis and inflammatory markers, but there were inconsistent associations with blood pressure, adiposity, insulin resistance, and blood lipids. CONCLUSIONS Our findings suggest that higher dietary intake and higher blood concentrations of lutein are generally associated with better cardiometabolic health. However, evidence mainly comes from observational studies in adults, whereas large-scale intervention studies and studies of lutein during pregnancy and childhood are scarce.

Randomized Placebo-Controlled Trial Assessing a Treatment Strategy Consisting of Pravastatin, Vitamin E, and Homocysteine Lowering on Plasma Asymmetric Dimethylarginine Concentration in Mild to Moderate CKD

BACKGROUND Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). The Anti-oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study showed that a multistep treatment strategy improved carotid intima-media thickness, endothelial function, and microalbuminuria in patients with stages 2 to 4 CKD. Increased plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been linked to greater CVD risk in patients with CKD. The aim of this study is to assess effects of the multistep intervention on plasma ADMA concentrations in the ATIC Study. STUDY DESIGN Secondary analysis of a randomized double-blind placebo-controlled trial. SETTING & PARTICIPANTS 93 patients with creatinine clearance of 15 to 70 mL/min/1.73 m(2) (according to the Cockcroft-Gault equation) from 7 outpatient clinics in Amsterdam, The Netherlands. INTERVENTION The treatment group received sequential treatment consisting of pravastatin, 40 mg/d. After 6 months, vitamin E, 300 mg/d, was added, and after another 6 months, homocysteine-lowering therapy (folic acid, 5 mg/d; pyridoxine, 100 mg/d; and vitamin B(12), 1 mg/d, all in 1 tablet) were added and continued for another year. The control group received matching placebos. OUTCOME & MEASURES Plasma ADMA levels. RESULTS 36 participants (77%) in the treatment group and 38 (83%) in the placebo group completed the study. Mean ADMA and symmetric dimethylarginine concentrations in the total study population were 0.53 +/- 0.07 (SD) and 1.14 +/- 0.46 mumol/L, respectively. After 24 months, there was no overall effect of the treatment strategy on ADMA concentrations (beta = -0.006; P = 0.27). Analysis of separate treatment effects suggested that vitamin E significantly decreased ADMA levels by 4% in the treatment group compared with the placebo group (multiple adjusted P = 0.02). LIMITATIONS The study was a secondary analysis, power calculation was based on the primary end point of carotid intima-media thickness, mean plasma ADMA levels were relatively low. CONCLUSION Overall, a multistep treatment strategy consisting of pravastatin, vitamin E, and B vitamins had no effect on plasma ADMA levels in a stage 2 to 4 CKD population. This suggests that the beneficial effects of the intervention were not mediated by changes in ADMA levels. Possible ADMA-lowering effects of vitamin E deserve further attention.

Parental, fetal, and infant risk factors for preschool overweight: the Generation R Study

Background:Overweight has its origins largely in early life. We aimed to identify the most important parental, fetal, and infant risk factors of preschool overweight.Methods:In a prospective cohort study, among 3,610 Caucasian preschool children, we assessed the associations of 34 putative parental, fetal, and infant factors with overweight risk.Results:Higher maternal BMI, paternal BMI, and birth weight were associated with higher risk of preschool overweight (odds ratio (OR): 1.23, 95% confidence interval (CI): 1.10, 1.39; OR: 1.35, 95% CI: 1.19, 1.53; and OR: 2.71, 95% CI: 2.27, 3.25, respectively, per SD increase). The same model identified low household income (OR: 1.74, 95% CI: 1.24, 2.45), being female (OR: 1.55, 95% CI: 1.20, 2.01), and experiencing third-trimester accelerated growth (OR: 1.73, 95% CI: 1.24, 2.40) or postnatal accelerated growth (OR: 6.39, 95% CI: 4.54, 8.99) as risk factors for preschool overweight. Higher polyunsaturated fat intake at 14 mo was associated with a lower risk of preschool overweight (OR: 0.77, 95% CI: 0.62, 0.96 per SD).Conclusion:Parental anthropometrics and household income, fetal and infant accelerated growth, and infant dietary fat intake are the major risk factors for the development of preschool overweight. Further studies need to explore whether these risk factors could be potential targets for preventive interventions.

Levels of Antibodies Against Tissue Transglutaminase During Pregnancy Are Associated With Reduced Fetal Weight and Birth Weight

BACKGROUND & AIMS Celiac disease in pregnant women has been associated with poor growth of the fetus, but little is known about how the level of celiac disease affects fetal growth or birth outcomes. We assessed the associations between levels of antibodies against tissue transglutaminase (anti-tTG, a marker of celiac disease) and fetal growth and birth outcomes for pregnant women. METHODS We performed a population-based prospective birth cohort study of 7046 pregnant women. Serum samples were collected during the second trimester of pregnancy and analyzed for levels of anti-tTG. Based on these levels, the women were categorized into 3 groups: negative anti-tTG (≤0.79 U/mL; n = 6702), intermediate anti-tTG (0.8 to ≤6 U/mL; n = 308), or positive anti-tTG (>6 U/mL; n = 36). Data on fetal growth and birth outcomes were collected from ultrasound measurements and medical records. RESULTS Fetuses of women in the positive anti-tTG group weighed 16 g less than those of women in the negative anti-tTG group (95% confidence interval [CI], -32 to -1 g) during the second trimester and weighed 74 g less (95% CI, -140 to -8 g) during the third trimester. Newborns of women in the intermediate and positive anti-tTG groups weighed 53 g (95% CI, -106 to -1 g) and 159 g (95% CI, -316 to -1 g) less at birth, respectively, than those of women in the negative anti-tTG group. The reduction in birth weight in offspring of mothers in the intermediate anti-tTG group was 2-fold greater among mothers who carried HLA-DQ2 or -DQ8 than among those without HLA-DQ2 or -DQ8. CONCLUSIONS Levels of anti-tTG in pregnant women are inversely associated with fetal growth. Growth was reduced to the greatest extent in fetuses of women with the highest levels of anti-tTG (>6 U/mL). Birth weight was also reduced in women with intermediate levels of anti-tTG (0.8 to ≤6 U/mL) and further reduced in those carrying HLA-DQ2 and -DQ8.