Genome‐wide association studies in adults have identified variants in hydroxysteroid 17‐beta dehydrogenase 13 (HSD17B13) and mitochondrial amidoxime reducing component 1 (MTARC1) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T>TA in HSD17B13, rs2642438G>A in MTARC1, and rs738409C>G in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3). Genotype–histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T>TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7; 95% confidence interval, 0.6–0.9) and a lower grade of portal inflammation (p < 0.001). rs2642438G>A in MTARC1 was associated with a lower grade of hepatic steatosis (p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective ‐TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down‐regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1. Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.

To aim of this study was to evaluate characteristics of the retinal microvasculature, but particularly potential associations with classic and novel (endothelial function and low-grade inflammation)markers for cardiovascular risk, in a cohort of children with overweight and (morbid) obesity. Central retinal arteriolar equivalent(CRAE) and central retinal venular equivalent(CRVE) were assessed. CRAE was significantly lower and AVR significantly higher in children with morbid obesity than in children with overweight and normal weight(p < 0.01). CRVE did not differ significantly between the four weight categories. A multiple linear regression model with CRAE as dependent variable showed that only DBP z-score(β = −2.848,p = 0.029) and plasma glucose concentrations(β = 6.029,p = 0.019) contributed significantly to the variation in CRAE. Remarkably, despite a correlation between CRAE and circulating concentrations of the adhesion molecules VCAM-1 or ICAM-1, markers for inflammation and endothelial function did not contribute to the variation in CRAE. This is the first study showing in population of children with overweight and obesity that the retinal arteriolar microvasculature, but not venular diameter is aberrant, with increasing BMI z-score. CRAE was significantly associated with several cardiovascular risk markers, and multiple linear regression showed that a higher diastolic blood pressure z-score and lower fasting plasma glucose concentrations significantly contributed to the variance in CRAE.

Context Childhood obesity increases the risk of diseases as diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Objective To evaluate the prevalence of comorbidities in school-age children with obesity and to compare its prevalence and the effect of a lifestyle intervention between children in primary and secondary school and between boys and girls. Design Cross-sectional analysis and lifestyle intervention. Setting Centre for Overweight Adolescent and Children’s Healthcare. Patients Comorbidities were evaluated in 149 primary and 150 secondary school children with (morbid) obesity (162 girls). The effect of lifestyle intervention was studied in 82 primary and 75 secondary school children. Intervention One-year interdisciplinary lifestyle intervention. Results Insulin resistance (37%), impaired glucose tolerance (IGT) (3%), dyslipidemia (48%), hypertension (7%), and elevated liver transaminase levels (54%) were already common in primary school children. Glomerular hyperfiltration and insulin resistance were more prevalent in secondary school children. IGT was more prevalent in girls. The change in body mass index z score after intervention was greater in primary school children (primary vs secondary: −0.25 ± 0.32 vs −0.11 ± 0.47), even as the change in low-density lipoprotein cholesterol concentrations [primary vs secondary: −0.30 (interquartile range, −0.70 to 0.10) vs −0.10 (interquartile range, −0.40 to 0.30)] and systolic blood pressure z score (primary vs secondary: −0.32 ± 1.27 vs 0.24 ± 1.3). The change in body mass index z score, but not in comorbidities, was greater in boys (boys vs girls: −0.33 ± 0.45 vs −0.05 ± 0.31). Conclusions The presence of comorbidities is already evident in primary school children with obesity. The effect of a lifestyle intervention on these comorbidities is greater in primary compared with secondary school children, stressing the need for early interventions.