High-sensitivity C-reactive protein is a predictive factor of adiposity in children : results of the Identification and prevention of Dietary- and lifestyle-induced health Effects in Children and InfantS (IDEFICS) study

Background-Whereas cross-sectional studies have shown that obesity is associated with increased C-reactive protein (CRP) levels in children, little is known about the impact of low-grade inflammation on body mass changes during growth. Methods and Results-We assessed cross-sectionally and longitudinally the association of high-sensitivity (hs)-CRP levels with overweight/obesity and related cardiometabolic risk factors in the Identification and prevention of Dietary-and lifestyle-induced health Effects in Children and InfantS (IDEFICS) cohort. 16 224 children from 8 European countries (2 to 9 years) were recruited during the baseline survey (T0). After the exclusion of 7187 children because of missing hs-CRP measurements and 2421 because of drug use during the previous week, the analysis was performed on 6616 children (Boys=3347; Girls=3269; age=6.3 +/- 1.7 years). Of them, 4110 were reexamined 2 years later (T1). Anthropometric variables, blood pressure, hs-CRP, blood lipids, glucose and insulin were measured. The population at T0 was divided into 3 categories, according to the baseline hs-CRP levels. Higher hs-CRP levels were associated with significantly higher prevalence of overweight/obesity, body mass index (BMI) z-score and central adiposity indices (P values all <0.0001), and with higher blood pressure and lower HDL-cholesterol levels. Over the 2-year follow-up, higher baseline hs-CRP levels were associated with a significant increase in BMI z-score (P<0.001) and significantly higher risk of incident overweight/obesity. Conclusions-Higher hs-CRP levels are associated to higher body mass and overweight/obesity risk in a large population of European children. Children with higher baseline levels of hs-CRP had a greater increase in BMI z-score and central adiposity over time and were at higher risk of developing overweight/obesity during growth

Transcriptome analysis in blood cells from children reveals potential early biomarkers of metabolic alterations

OBJECTIVES: The development of effective strategies to prevent childhood obesity and its comorbidities requires new, reliable early biomarkers. Here, we aimed to identify in peripheral blood cells potential transcript-based biomarkers of unhealthy metabolic profile associated to overweight/obesity in children. METHODS: We performed a whole-genome microarray analysis in blood cells to identify genes differentially expressed between overweight and normal weight children to obtain novel transcript-based biomarkers predictive of metabolic complications. RESULTS: The most significant enriched pathway of differentially expressed genes was related to oxidative phosphorylation, for which most of genes were downregulated in overweight versus normal weight children. Other genes were involved in carbohydrate metabolism/glucose homoeostasis or in lipid metabolism (for example, TCF7L2, ADRB3, LIPE, GIPR), revealing plausible mechanisms according to existing biological knowledge. A set of differentially expressed genes was identified to discriminate in overweight children those with high or low triglyceride levels. CONCLUSIONS: Functional microarray analysis has revealed a set of potential blood-cell transcript-based biomarkers that may be a useful approach for early identification of children with higher predisposition to obesity-related metabolic alterations

Blood cells as a source of transcriptional biomarkers of childhood obesity and its related metabolic alterations: results of the IDEFICS Study

Background: IDEFICS (Identification and Prevention of Dietary-and Lifestyle-Induced Health Effects in Children and Infants Project) is a European multicenter study on childhood obesity. One of its goals is to define early biomarkers of risk associated with obesity and its comorbid conditions. Objective: We considered blood cells as a new potential source of transcriptional biomarkers for these metabolic disorders and examined whether blood cell mRNA levels of some selected genes (LEPR, INSR, CPT1A, SLC27A2, UCP2, FASN, and PPAR alpha) were altered in overweight children and whether their expression levels could be defined as markers of the insulin-resistant or dyslipidemic state associated with overweight. Design: Blood samples were obtained from 306 normal-weight and overweight children, aged 2-9 yr, from eight different European countries. Whole-blood mRNA levels were assessed by quantitative RT-PCR. Results: LEPR, INSR, and CPT1A mRNA levels were higher in overweight compared with normal-weight children (the two latter only in males), whereas SLC27A2 mRNA levels were lower in overweight children. Significant associations were also found between expression levels of LEPR, INSR, CPT1A, SLC27A2, FASN, PPAR alpha, and different parameters, including body mass index, homeostasis model assessment index, and plasma triglycerides and cholesterol levels. These associations showed that high expression levels of CPT1A, SLC27A2, INSR, FASN, or PPAR alpha may be indicative of a lower risk for the insulin-resistant or dyslipidemic state associated with obesity, whereas low LEPR mRNA levels appear as a marker of high low-density lipoprotein cholesterol, independently of body mass index. Conclusions: These findings point toward the possibility of using the expression levels of these genes in blood cells as markers of metabolic status and can potentially provide an early warning of a future disorder

Longitudinal associations of lifestyle factors and weight status with insulin resistance (HOMA-IR) in preadolescent children : the large prospective cohort study IDEFICS

Background: This study investigates prospective associations of anthropometrical and lifestyle indices with insulin resistance (IR) in European children from the IDEFICS cohort. Insulin resistance (IR) is a growing concern in childhood obesity and a central aspect of the metabolic syndrome (MS). It most likely represents the link between obesity and type 2 diabetes. Methods: This longitudinal study included 3348 preadolescent children aged 3 to 10.9 years from 8 European countries who were observed from 2007/2008 to 2009/2010. The main outcome measure in the present analysis is HOMA-IR (homeostasis model assessment as a common proxy indicator to quantify IR) at follow-up and in its longitudinal development. Anthropometrical measures and lifestyle indices, including objectively determined physical activity, were considered, among others factors, as determinants of IR. Prospective associations between IR at follow-up and anthropometrical and lifestyle indices were estimated by logistic regression models. Results: Country-specific prevalence rates of IR in the IDEFICS cohort of European children showed a positive trend with weight category. Prospective multivariate analyses showed the strongest positive associations of IR with BMI z-score (OR = 2.6 for unit change from the mean, 95 % CI 2.1-3.1) and z-score of waist circumference (OR = 2.2 for unit change from the mean, 95 % CI 1.9-2.6), which were analysed in separate models, but also for sex (OR = 2.2 for girls vs. boys, 95 % CI 1.5-3.1 up to OR 2.5, 95 % CI 1.8-3.6 depending on the model), audio-visual media time (OR = 1.2 for an additional hour per day, 95 % CI 1.0-1.4 in both models) and an inverse association of objectively determined physical activity (OR = 0.5 for 3rd compared to 1st quartile, 95 % CI 0.3-0.9 in both models). A longitudinal reduction of HOMA-IR was accompanied with a parallel decline in BMI. Conclusions: This study is, to our knowledge, the first prospective study on IR in a preadolescent children's population. It supports the common hypothesis that overweight and obesity are the main determinants of IR. Our data also indicate that physical inactivity and a sedentary lifestyle are likewise associated with the development of IR, independent of weight status. The promotion of physical activity should thus be considered as an equal option to dietary intervention for the treatment of IR in the paediatric practice

Blood lipids among young children in Europe : results from the European IDEFICS study

BACKGROUND: Measurement of cholesterol and triglyceride (TG) fractions in blood has become standard practice in the early detection of atherosclerotic disease pathways. Considerable attention is given nowadays to the presence of these risk factors in children and to start preventive campaigns early in life. In this context, it is imperative to have valid comparative frameworks for interpretation of lipid levels. The aim of this study is to present sex-and age-specific reference values on blood lipid levels in European children aged 2.0-10.9 years. METHODS: Fasting blood was obtained via either venipuncture or capillary sampling. In 13 579 European non-obese children (50.3% boys), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), TG and TC/HDL-C ratio levels were measured with a point-of-care analyser (Cholestech). Sex- and age-specific reference values were computed with the GAMLSS method with the statistical software R. RESULTS: Reference curves and 1st, 3rd, 10th, 25th, 50th, 75th, 90th, 97th and 99th percentile values are presented. HDL-C showed a positive trend with age, from 2 years onwards, but was relatively stable above the age of 7. For LDL-C and TC, linear but small age-related trends were seen. The TC/HDL-C values showed a gradual negative trend from the age of 2 up to 6 and were relatively stable afterwards. For TG, no age trend was found (P = 0.285). Boys had higher mean HDL-C values than girls (1.414 vs 1.368 mmol l(-1)), and lower TC, LDL-C, TC/HDL-C and TG values (3.981 vs 4.087 mmol l(-1); 2.297 vs 2.435 mmol l(-1); 2.84 vs 3.01mmol l(-1); and 0.509 vs 0.542 mmol l(-1), respectively). CONCLUSIONS: These new and recent references could serve as a European orientation of blood lipid values in children in the context of standard medical practice and for the purpose of public health screening

Pcl-PRC2 is needed to generate high levels of H3-K27 trimethylation at Polycomb target genes

PRC2 is thought to be the histone methyltransferase (HMTase) responsible for H3-K27 trimethylation at Polycomb target genes. Here we report the biochemical purification and characterization of a distinct form of Drosophila PRC2 that contains the Polycomb group protein polycomblike (Pcl). Like PRC2, Pcl-PRC2 is an H3-K27-specific HMTase that mono-, di- and trimethylates H3-K27 in nucleosomes in vitro. Analysis of Drosophila mutants that lack Pcl unexpectedly reveals that Pcl-PRC2 is required to generate high levels of H3-K27 trimethylation at Polycomb target genes but is dispensable for the genome-wide H3-K27 mono- and dimethylation that is generated by PRC2. In Pcl mutants, Polycomb target genes become derepressed even though H3-K27 trimethylation at these genes is only reduced and not abolished, and even though targeting of the Polycomb protein complexes PhoRC and PRC1 to Polycomb response elements is not affected. Pcl-PRC2 is thus the HMTase that generates the high levels of H3-K27 trimethylation in Polycomb target genes that are needed to maintain a Polycomb-repressed chromatin state

C-reactive protein reference percentiles among pre-adolescent children in Europe based on the IDEFICS study population

OBJECTIVES: C-reactive protein (CRP) is involved in a wide range of diseases. It is a powerful marker for inflammatory processes used for diagnostic and monitoring purposes. We aimed to establish reference values as data on the distribution of serum CRP levels in young European children are scarce. SUBJECTS: Reference values of high-sensitivity CRP concentrations were calculated for 9855 children aged 2.0-10.9 years, stratified by age and sex. The children were recruited during the population-based European IDEFICS study (Identification and prevention of Dietary-and lifestyle-induced health Effects in Children and infantS) with 18 745 participants recruited from 2007 to 2010. RESULTS: In 44.1 % of the children, CRP values were below or equal the detection limit of 0.2 mg/l. Median CRP concentrations showed a slight negative age trend in boys and girls, whereas serum CRP values were slightly higher in girls than in boys across all age groups. CONCLUSIONS: Our population-based reference values of CRP may guide paediatric practice as elevated values may require further investigation or treatment. Therefore, the presented reference values represent a basis for clinical evaluation and for future research on risk assessment of diseases associated with increased CRP levels among children

Percentiles of fasting serum insulin, glucose, HbA1c and HOMA-IR in pre-pubertal normal weight European children from the IDEFICS cohort

OBJECTIVES: The aim of this study is to present age-and sex-specific reference values of insulin, glucose, glycosylated haemoglobin (HbA1c) and the homeostasis model assessment to quantify insulin resistance (HOMA-IR) for pre-pubertal children. METHODS: The reference population consists of 7074 normal weight 3- to 10.9-year-old pre-pubertal children from eight European countries who participated in at least one wave of the IDEFICS ('identification and prevention of dietary-and lifestyle-induced health effects in children and infants') surveys (2007-2010) and for whom standardised laboratory measurements were obtained. Percentile curves of insulin (measured by an electrochemiluminescence immunoassay), glucose, HbA1c and HOMA-IR were calculated as a function of age stratified by sex using the general additive model for location scale and shape (GAMLSS) method. RESULTS: Levels of insulin, fasting glucose and HOMA-IR continuously show an increasing trend with age, whereas HbA1c shows an upward trend only beyond the age of 8 years. Insulin and HOMA-IR values are higher in girls of all age groups, whereas glucose values are slightly higher in boys. Median serum levels of insulin range from 17.4 and 13.2 pmol l(-1) in 3-< 3.5-year-old girls and boys, respectively, to 53.5 and 43.0 pmol l(-1) in 10.5-< 11-year-old girls and boys. Median values of glucose are 4.3 and 4.5 mmol l(-1) in the youngest age group and 49.3 and 50.6 mmol l(-1) in the oldest girls and boys. For HOMA-IR, median values range from 0.5 and 0.4 in 3-< 3.5-year-old girls and boys to 1.7 and 1.4 in 10.5-< 11-year-old girls and boys, respectively. CONCLUSIONS: Our study provides the first standardised reference values for an international European children's population and provides the, up to now, largest data set of healthy pre-pubertal children to model reference percentiles for markers of insulin resistance. Our cohort shows higher values of Hb1Ac as compared with a single Swedish study while our percentiles for the other glucose metabolic markers are in good accordance with previous studies