Association of adipocytokine pathway gene polymorphisms with NAFLD in obese children. / è„‚è‚ªç»†èƒžå› å­é€šè·¯åŸºå› å¤šæ€æ€§ä¸Žè‚¥èƒ–å„¿ç«¥éžé ’ç²¾æ€§è„‚è‚ªæ€§è‚ç— çš„å ³è”.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) has significant genetic susceptibility. Adipocytokines play a crucial role in NAFLD development by participating in insulin resistance and hepatic steatosis. However, the association between adipocytokine pathway genes and NAFLD remains unclear. This study aims to explore the association of gene polymorphisms in the adipocytokine pathway and their interactions with NAFLD in obese children. METHODS: A case-control study was conducted, dividing obese children into NAFLD and control groups. Peripheral venous blood (2 mL) was collected from each participant for DNA extraction. A total of 14 single nucleotide polymorphisms (SNP) in the adipocytokine pathway were genotyped using multiplex PCR and high-throughput sequencing. Univariate and multivariate Logistic regression analyses were used to assess the association between SNP and NAFLD in obese children. Dominant models were used to analyze additive and multiplicative interactions via crossover analysis and Logistic regression. Generalized multifactor dimensionality reduction (GMDR) was used to detect gene-gene interactions among the 14 SNPs and their association with NAFLD in obese children. RESULTS: A total of 1 022 children were included, with 511 in the NAFLD group and 511 in the control group. After adjusting for age, gender, and BMI, multivariate Logistic regression showed that PPARG rs1801282 was associated with NAFLD in the obese children in 3 genetic models: heterozygote model (CG vs CC, OR=0.58, 95% CI 0.36 to 0.95, P=0.029), dominant model (GG+CG vs CC, OR=0.62, 95% CI 0.38 to 1.00, P=0.049), and overdominant model (CC+GG vs CG, OR=1.72, 95% CI 1.06 to 2.80, P=0.028). PRKAG2 rs12703159 was associated with NAFLD in 4 genetic models: heterozygous model (CT vs CC, OR=1.51, 95% CI 1.10 to 2.07, P=0.011), dominant model (CT+TT vs CC, OR=1.50, 95% CI 1.10 to 2.03, P=0.010), overdominant model (CC+TT vs CT, OR=0.67, 95% CI 0.49 to 0.92, P=0.012), and additive model (CC vs CT vs TT, OR=1.40, 95% CI 1.07 to 1.83, P=0.015). No significant multiplicative or additive interaction between PPARG rs1801282 and PRKAG2 rs12703159 was found in association with NAFLD. GMDR analysis, adjusted for age, gender, and BMI, revealed no statistically significant interactions among the 14 SNPs (all P>0.05). CONCLUSIONS: Mutations in PPARG rs1801282 and PRKAG2 rs12703159 are associated with NAFLD in obese children. However, no gene-gene interactions among the SNP are found to be associated with NAFLD in obese children.

Association of whole blood copper, zinc, calcium, magnesium, and iron with non-alcoholic fatty liver disease in overweight and obese children. / å ¨è¡€é“œã€é”Œã€é’™ã€é•ã€é“ä¸Žè¶ é‡è‚¥èƒ–å„¿ç«¥éžé ’ç²¾æ€§è„‚è‚ªè‚ç— çš„å ³è”.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder in overweight and obese children, and its etiology and pathogenesis remain unclear, lacking effective preventive and therapeutic measures. This study aims to explore the association between whole blood copper, zinc, calcium, magnesium and iron levels and NAFLD in overweight and obese children aged 6 to 17 years, providing a scientific basis for the prevention and intervention of early NAFLD in overweight and obese children. METHODS: A cross-sectional study design was used to collect relevant data from overweight and obese children who visited the Hunan Children's Hospital from January 2019 to December 2021 through questionnaire surveys. Fasting blood samples were collected from the subjects, and various indicators such as blood glucose, blood lipid, and mineral elements were detected. All children were divided into an overweight group (n=400) and a NAFLD group (n=202). The NAFLD group was divided into 2 subgroups according to the ALT level: A non-alcoholic fatty liver (NAFL) group and a non-alcoholic steatohepatitis (NASH) group. Logistic regression analysis was used to analyze the association between minerals (copper, zinc, calcium, magnesium, and iron) and NAFLD, NAFL and NASH. RESULTS: A total of 602 subjects were included, of whom 73.6% were male, with a median age of 10 (9, 11) years, and a body mass index (BMI) of 24.9 (22.7, 27.4) kg/m2. The intergroup comparison results showed that compared with the overweight group, the NAFLD group had higher levels of age, BMI, diastolic blood pressure (DBP), systolic blood pressure (SBP), triglyceride (TG), low density lipoprotein (LDL), alanine transaminase (ALT) and aspartate aminotransferase (AST), and lower level of high density lipoprotein (HDL). The NAFL group had higher levels of age, BMI, DBP, SBP, ALT, and AST, and lower levels of HDL compared with the overweight group. The levels of age, BMI, DBP, SBP, TG, LDL, ALT, and AST of NASH were higher than those in the overweight group, while the level of HDL was lower than that in overweight group (all P<0.017). After adjusting for a variety of confounders, the OR of NAFLD for the highest quantile of iron was 1.79 (95% CI 1.07 to 3.00) compared to the lowest quantile, and no significant association was observed between copper, zinc, calcium, and magnesium, and NAFLD. The subgroup analysis of NAFLD showed that the OR for the highest quantile of iron in children with NAFL was 2.21 (95% CI 1.26 to 3.88), while no significant association was observed between iron level and NASH. In addition, no significant associations were observed between copper, zinc, calcium, and magnesium levels and NAFL or NASH. CONCLUSIONS: High iron level increases the risk of NAFLD (more likely NAFL) in overweight and obese children, while copper, zinc, calcium, magnesium, and other elements are not associated with the risk of NAFLD in overweight and obese children.

Clinical characteristics and follow-up of complex arrhythmias associated with RYR2 gene mutations in children.

Objective: The aim of this study was to analyze the diagnosis, treatment, and follow-up of six cases of complex arrhythmias associated with RYR2 gene mutations in children. Method: A retrospective analysis was conducted on six children diagnosed with complex arrhythmias associated with RYR2 gene mutations. The study included an analysis of the age of onset, initial symptoms, electrocardiographic characteristics, genetic results, treatment course, and follow-up outcomes. Results: Among the six cases included in the study, there were four males and two females, with an average age of 3.5 ± 0.5 years. The average time from initial symptoms to diagnosis was 2.7 ± 1.3 years. The most common clinical manifestation was syncope, with exercise and emotions being the main triggers. All six children had de novo missense mutations in the RYR2 gene identified through whole-exome sequencing. In Holter electrocardiogram, atrial arrhythmias and sinoatrial node dysfunction were commonly observed in younger children. Four patients underwent exercise stress testing, with two experiencing bidirectional ventricular premature contractions and two experiencing bidirectional ventricular tachycardia and polymorphic ventricular tachycardia. Initial treatment involved oral propranolol or metoprolol. If arrhythmias persisted, flecainide or propafenone was added as adjunctive therapy. Two patients received permanent cardiac pacemaker treatment (single chamber ventricular pacemaker, VVI). All patients survived, with three experiencing occasional syncope during treatment. The follow-up period ranged from 12 to 37 months, with an average follow-up time of 24.3 ± 3.7 months. Conclusion: Complex arrhythmias associated with RYR2 gene mutations in children can present with various clinical manifestations. Atrial arrhythmias combined with sinoatrial node dysfunction are commonly observed in younger children, and the combination of pharmacological therapy and cardiac pacemaker treatment yields favourable treatment outcomes.

Cultivated Enterococcus faecium B6 from children with obesity promotes nonalcoholic fatty liver disease by the bioactive metabolite tyramine.

Gut microbiota plays an essential role in nonalcoholic fatty liver disease (NAFLD). However, the contribution of individual bacterial strains and their metabolites to childhood NAFLD pathogenesis remains poorly understood. Herein, the critical bacteria in children with obesity accompanied by NAFLD were identified by microbiome analysis. Bacteria abundant in the NAFLD group were systematically assessed for their lipogenic effects. The underlying mechanisms and microbial-derived metabolites in NAFLD pathogenesis were investigated using multi-omics and LC-MS/MS analysis. The roles of the crucial metabolite in NAFLD were validated in vitro and in vivo as well as in an additional cohort. The results showed that Enterococcus spp. was enriched in children with obesity and NAFLD. The patient-derived Enterococcus faecium B6 (E. faecium B6) significantly contributed to NAFLD symptoms in mice. E. faecium B6 produced a crucial bioactive metabolite, tyramine, which probably activated PPAR-γ, leading to lipid accumulation, inflammation, and fibrosis in the liver. Moreover, these findings were successfully validated in an additional cohort. This pioneering study elucidated the important functions of cultivated E. faecium B6 and its bioactive metabolite (tyramine) in exacerbating NAFLD. These findings advance the comprehensive understanding of NAFLD pathogenesis and provide new insights for the development of microbe/metabolite-based therapeutic strategies.