Thomas Reinehr

Two new Loci for body-weight regulation identified in a joint analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85×10−8 in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84×10−7), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at ∼1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.

Promotion and provision of drinking water in schools for overweight prevention: randomized, controlled cluster trial.

OBJECTIVE. The study tested whether a combined environmental and educational intervention solely promoting water consumption was effective in preventing overweight among children in elementary school. METHODS. The participants in this randomized, controlled cluster trial were second- and third-graders from 32 elementary schools in socially deprived areas of 2 German cities. Water fountains were installed and teachers presented 4 prepared classroom lessons in the intervention group schools (N = 17) to promote water consumption. Control group schools (N = 15) did not receive any intervention. The prevalence of overweight (defined according to the International Obesity Task Force criteria), BMI SD scores, and beverage consumption (in glasses per day; 1 glass was defined as 200 mL) self-reported in 24-hour recall questionnaires, were determined before (baseline) and after the intervention. In addition, the water flow of the fountains was measured during the intervention period of 1 school year (August 2006 to June 2007). RESULTS. Data on 2950 children (intervention group: N = 1641; control group: N = 1309; age, mean ± SD: 8.3 ± 0.7 years) were analyzed. After the intervention, the risk of overweight was reduced by 31% in the intervention group, compared with the control group, with adjustment for baseline prevalence of overweight and clustering according to school. Changes in BMI SD scores did not differ between the intervention group and the control group. Water consumption after the intervention was 1.1 glasses per day greater in the intervention group. No intervention effect on juice and soft drink consumption was found. Daily water flow of the fountains indicated lasting use during the entire intervention period, but to varying extent. CONCLUSION. Our environmental and educational, school-based intervention proved to be effective in the prevention of overweight among children in elementary school, even in a population from socially deprived areas.

Insulin sensitivity among obese children and adolescents, according to degree of weight loss.

Objective. Insulin sensitivity is impaired among some obese children, reflecting an atherogenic risk factor profile for the affected subjects. This study was performed to examine the amount of weight reduction required to improve insulin sensitivity. Methods. We studied changes in insulin sensitivity indices (ISIs) for glucose metabolism (homeostasis model assessment and quantitative insulin sensitivity check index) and fat metabolism (free fatty acids) during a 1-year period among obese children who attended an obesity intervention program. The children were divided into 4 groups according to their changes in body mass index (BMI) SD score (SDS), as follows: group I, decrease in SDS-BMI of ≥0.5; group II, decrease in SDS-BMI of ≥0.25 to <0.5; group III, decrease in SDS-BMI of <0.25; group IV, increase in SDS-BMI. Results. Fifty-seven obese children (age range: 6–14 years; median age: 10 years; 46% boys) were included in the study. The 4 groups did not differ with respect to age, gender, degree of overweight (SDS-BMI), or ISI values at baseline. An increase in SDS-BMI (group IV, n = 12) was followed by a significant decrease in ISI values. The ISIs improved for group I (n = 9), whereas there were no significant changes in these parameters for group II (n = 21) and group III (n = 15). Conclusions. During a 1-year period, an increase in weight among obese children was associated with a decrease in insulin sensitivity. Weight loss was followed by significant improvement in insulin sensitivity for glucose and fat metabolism but only if the SDS-BMI decreased by ≥0.5 during the 1-year period.

Changes in self-reported and parent-reported health-related quality of life in overweight children and adolescents participating in an outpatient training: findings from a 12-month follow-up study

BackgroundHealth-related quality of life (HRQoL) was found to improve in participants of weight management interventions. However, information on moderately overweight youth as well as on maintaining HRQoL improvements following treatment is sparse. We studied the HRQoL of 74 overweight, but not obese participants (32.4% male, mean age = 11.61 ± 1.70 SD) of a comprehensive and effective six-month outpatient training at four time-points up to 12 months after end of treatment.MethodsHRQoL was measured by self-report and proxy-report versions of the generic German KINDL-R, including six sub domains, and an obesity-specific additional module. Changes in original and z-standardized scores were analyzed by (2×4) doubly multivariate analysis of variance. This was done separately for self- and proxy-reported HRQoL, taking into account further socio-demographic background variables and social desirability. Additionally, correlations between changes in HRQoL scores and changes in zBMI were examined.ResultsThere were significant multivariate time effects for self-reported and proxy-reported HRQoL and a significant time-gender interaction in self-reports revealed (p < .05). Improvements in weight-specific HRQoL were evident during treatment (partial η2 = 0.14-0.19). Generic HRQoL further increased after end of treatment. The largest effects were found on the dimension self-esteem (partial η2 = 0.08-0.09 for proxy- and self-reported z-scores, respectively). Correlations with changes in weight were gender-specific, and weight reduction was only associated with HRQoL improvements in girls.ConclusionsPositive effects of outpatient training on generic and weight-specific HRQoL of moderately overweight (not obese) children and adolescents could be demonstrated. Improvements in HRQoL were not consistently bound to weight reduction. While changes in weight-specific HRQoL were more immediate, generic HRQoL further increased after treatment ended. An extended follow-up may therefore be needed to scrutinize HRQoL improvements due to weight management.Trial registrationclinicaltrials.gov NCT00422916

Vitamin D status and parathyroid hormone in obese children before and after weight loss

OBJECTIVE The roles of vitamin D and parathyroid hormone (PTH) are discussed controversially in obesity, and studies of these hormones in obese children are limited. Therefore, we studied the relationships between PTH, 1,25-dihydroxy-vitamin D (1,25-OH Vit D), 25-hydroxy-vitamin D (25-OH Vit D), weight status, and insulin sensitivity before and after weight loss in obese children. METHODS Fasting serum PTH, 1,25-OH Vit D, 25-OH Vit D, inorganic phosphate, calcium, alkaline phosphatase (AP), insulin, glucose, and weight status (SDS-BMI and percentage body fat) were determined in 133 obese children (median age 12.1 years) and compared with 23 non-obese children. Furthermore, these parameters were analyzed in 67 obese children before and after participating in a 1-year obesity intervention program. RESULTS Obese children had significantly (P < 0.001) higher PTH and lower 25-OH Vit D concentrations compared with non-obese children, while calcium, phosphate, AP, and 1,25-OH Vit D did not differ significantly. Changes of PTH (r = 0.23, P = 0.031) and 25-OH Vit D (r = -0.27, P = 0.013) correlated significantly with changes of SDS-BMI, but not with changes of insulin sensitivity (homeostasis model assessment; HOMA-B%). Reduction of overweight in 35 children led to a significant (P < 0.01) decrease of PTH concentrations and an increase in 25-OH Vit D levels. CONCLUSIONS PTH levels were positively and 25-OH Vit D concentrations were negatively related to weight status. Since these alterations normalized after weight loss, these changes are consequences rather than causes of overweight. A relationship between PTH, vitamin D, and insulin sensitivity based on the HOMA index was not found in obese children. Further longitudinal clamp studies are necessary to study the relationship between vitamin D and insulin sensitivity.

Cardiovascular risk in 26,008 European overweight children as established by a multicenter database.

Objective: Although the obesity epidemic is progressing in European children too, there is no consensus on the population‐specific prevalence of comorbidities or efficient diagnostic strategies. Therefore, weight‐related risk factors, their interrelationship, and association with biological parameters were assessed in a large group of overweight (OW) children, documented by an electronic database.

Fetuin-A and Its Relation to Metabolic Syndrome and Fatty Liver Disease in Obese Children Before and After Weight Loss

CONTEXT There are very limited data available concerning the relationships between fetuin-A, weight status, nonalcoholic fatty liver disease (NAFLD), and features of the metabolic syndrome (MetS) in obese humans, and especially in children. OBJECTIVE Our objective was to study the longitudinal relationships between fetuin-A, NAFLD, and MetS in obese children. DESIGN This was a 1-yr longitudinal follow-up study. SETTING This study was performed in primary care. PATIENTS A total of 36 obese and 14 lean children was included in the study. INTERVENTION An outpatient 1-yr intervention program based on exercise, behavior, and nutrition therapy was performed. MAIN OUTCOME MEASURES Changes of weight status (sd score-body mass index), waist circumference, fetuin-A, blood pressure, lipids, transaminases, insulin resistance index homeostasis model assessment (HOMA), and prevalence of NAFLD (defined by liver ultrasound) were calculated. RESULTS The 12 obese children with NAFLD had significantly higher fetuin-A levels (0.35+/-0.07 g/liter) than the 24 obese children without NAFLD (0.29+/-0.06 g/liter) and the 14 normal weight children (0.29+/-0.05 g/liter). Fetuin-A levels were independent of age, pubertal stage, and gender. Fetuin-A correlated significantly to systolic (r=0.50) and diastolic blood pressure (r=0.41), insulin resistance index HOMA (r=0.28), and high-density lipoprotein-cholesterol (r=-0.31). Changes of fetuin-A correlated significantly to changes of insulin resistance index HOMA (r=0.34), systolic (r=0.31) and diastolic blood pressure (r=0.37), and waist circumferences (r=0.36). Substantial weight loss in 21 children led to a significant decrease of fetuin-A and the prevalence of NAFLD in contrast to the 15 children without substantial weight loss. CONCLUSIONS Fetuin-A levels were higher in children with NAFLD, and were related to insulin resistance and to features of the MetS in both cross-sectional and longitudinal analyses. Therefore, fetuin-A might be a new promising link between obesity and its comorbidities.

Intima-Media Thickness in Obese Children Before and After Weight Loss

OBJECTIVE. Obesity in childhood is related to increased intima-media thickness, a noninvasive marker for early atherosclerotic changes. The objective of this study was to analyze the changes of intima-media thickness in obese children with weight loss. METHODS. We analyzed the changes of intima-media thickness and, as markers of cardiovascular risk factor profile, systolic and diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol, glucose, insulin, and insulin resistance index (homeostasis model analysis) in 56 prepubertal obese children (median: 9 years old) before and after a 1-year outpatient intervention program. The control group consisted of 10 nonobese children of the same age and gender. We determined the carotid intima-media thickness by B-mode ultrasound with a 14-MHz linear transducer. Substantial weight loss was defined by a reduction of overweight of at least 0.5 standard deviation scores in BMI. RESULTS. Obese children demonstrated a significantly thicker intima-media compared with the control group. Furthermore, blood pressure, triglycerides, insulin, and insulin resistance index were significantly higher in obese children, whereas high-density lipoprotein cholesterol was significantly lower. In the 24 obese children with substantial weight loss, intima-media thickness, blood pressure, triglycerides, insulin, and insulin resistance index decreased significantly, whereas high-density lipoprotein cholesterol increased significantly. In the 32 obese children without substantial weight loss, there were no significant changes apart from an increase of insulin and insulin resistance index. CONCLUSIONS. Because obese children demonstrated a thicker intima-media, vascular changes seemed to occur already in childhood obesity. Paralleling the improvement of the cardiovascular risk factor profile, intima-media thickness decreased in obese children with substantial weight loss, suggesting the reversibility of early atherosclerotic changes.

Comparison of metabolic syndrome prevalence using eight different definitions: A critical approach

Objective: Multiple definitions of the metabolic syndrome (MS) have been proposed for children, adolescents and adults. The aim of this study was to analyse the variations in the MS prevalence using different definitions and to examine which factors influence the frequency of the MS in childhood and adolescence. Methods and design: The prevalence of the MS according to eight proposed definitions was studied in 1205 Caucasian overweight children and adolescents aged 4–16 years (mean body mass index (BMI) 27.3 kg/m2, mean age 11.8 years, 46% males, 39% prepubertal). Blood pressure, waist circumference and fasting triglycerides, HDL-cholesterol, total cholesterol, insulin and glucose concentrations were determined. Overweight was defined according to the International Task Force of Obesity in Childhood. Degree of overweight was calculated as standard deviation score of BMI (SDS-BMI). Insulin resistance was estimated based on the HOMA model. Results: The prevalence of the MS varied significantly (p<0.001), being between 6% and 39% depending on the different definitions. Only 2% of the children fulfilled the criteria of the MS in all definitions. Insulin resistance and degree of overweight were associated with the MS. In most definitions, pubertal stage did not influence the occurrence of the MS. In a principal component analysis, total cholesterol, triglycerides and waist circumference showed high final communality estimates. Conclusions: Since the prevalence of the MS varied widely in overweight children and adolescents depending on the proposed definition used, an internationally accepted uniform definition of the MS is necessary to compare different populations and studies.

Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease

BACKGROUND A single nucleotide polymorphism (SNP) rs599839 located at chromosome 1p13.3 has previously been associated with risk of coronary artery disease (CAD) and with serum levels of low-density lipoprotein cholesterol (LDL-C). A functional link explaining the association of SNP rs599839 with LDL-C levels and CAD risk has not yet been elucidated. METHODS We analyzed the association of rs599839 with LDL-C in 6605 individuals across a wide age spectrum and with CAD in four case-control studies comprising 4287 cases and 7572 controls. Genome-wide expression array data was used to assess the association of SNP rs599839 with gene expression at chromosome 1p13. Finally, we overexpressed sortilin in transfected cells to study LDL-uptake in vitro. RESULTS Each copy of the G-allele of rs599839 associated with a decrease of serum LDL-C by 0.14 mmol/L (90% confidence interval (CI) 0.09-0.17 mmol/L, p=2.6 x 10(-11)). Moreover, each copy of the G-allele associated with a 9% decrease of CAD risk (90% CI 4-14%) in the presently studied four case-control samples and with a 13% decrease (90% CI 10-17%, p=2.18 x 10(-9)) in a pooled meta-analysis including recent genome-wide association studies on CAD. The same allele was associated with higher mRNA-expression levels of the multiligand receptor sortilin (log transformed mRNA AA vs. GG=8.31 vs. 8.55; p=0.01). Overexpression of SORT1 cDNA resulted in a significant increase in LDL-particle uptake (+23%, p=0.01). CONCLUSIONS Rs599839 associates with decreased LDL-C and a lower risk of CAD. Effects appear to be mediated by increased sortilin expression and subsequently enhanced LDL-uptake into cells.