Establish a noninvasive model to screen metabolic dysfunction-associated steatotic liver disease in children aged 6-14 years in China and its applications in high-obesity-risk countries and regions.

Background: The prevalence of metabolic-associated steatotic liver disease (MASLD) is rising precipitously among children, particularly in regions or countries burdened with high prevalence of obesity. However, identifying those at high risk remains a significant challenge, as the majority do not exhibit distinct symptoms of MASLD. There is an urgent need for a widely accepted non-invasive predictor to facilitate early disease diagnosis and management of the disease. Our study aims to 1) evaluate and compare existing predictors of MASLD, and 2) develop a practical screening strategy for children, tailored to local prevalence of obesity. Methods: We utilized a school-based cross-sectional survey in Beijing as the training dataset to establish predictive models for screening MASLD in children. An independent school-based study in Ningbo was used to validate the models. We selected the optimal non-invasive MASLD predictor by comparing logistic regression model, random forest model, decision tree model, and support vector machine model using both the Beijing and Ningbo datasets. This was followed by serial testing using the best performance index we identified and indices from previous studies. Finally, we calculated the potential MASLD screening recommendation categories and corresponding profits based on national and subnational obesity prevalence, and applied those three categories to 200 countries according to their obesity prevalence from 1990 to 2022. Findings: A total of 1018 children were included (NBeijing = 596, NNingbo = 422). The logistic regression model demonstrated the best performance, identifying the waist-to-height ratio (WHtR, cutoff value ≥0.48) as the optimal noninvasive index for predicting MASLD, with strong performance in both training and validation set. Additionally, the combination of WHtR and lipid accumulation product (LAP) was selected as an optimal serial test to improve the positive predictive value, with a LAP cutoff value of ≥668.22 cm × mg/dL. Based on the obesity prevalence among 30 provinces, three MASLD screening recommendations were proposed: 1) "Population-screening-recommended": For regions with an obesity prevalence ≥12.0%, where MASLD prevalence ranged from 5.0% to 21.5%; 2) "Resources-permitted": For regions with an obesity prevalence between 8.4% and 12.0%, where MASLD prevalence ranged from 2.3% to 4.4%; 3) "Population-screening-not-recommended": For regions with an obesity prevalence <8.4%, where MASLD prevalence is difficult to detect using our tool. Using our proposed cutoff for screening MASLD, the number of countries classified into the "Population-screening-recommended" and "Resources-permitted" categories increased from one and 11 in 1990 to 95 and 28 in 2022, respectively. Interpretation: WHtR might serve as a practical and accessible index for predicting pediatric MASLD. A WHtR value ≥0.48 could facilitate early identification and management of MASLD in areas with obesity prevalence ≥12.0%. Furthermore, combining WHtR ≥0.48 with LAP ≥668.22 cm × mg/dL is recommended for individual MASLD screening. Moreover, linking these measures with population obesity prevalence not only helps estimate MASLD prevalence but also indicates potential screening profits in regions at varying levels of obesity risk. Funding: This study was supported by grants from Capital's Funds for Health Improvement and Research (Grant No. 2022-1G-4251), National Natural Science Foundation of China (Grant No. 82273654), Major Science and Technology Projects for Health of Zhejiang Province (Grant No. WKJ-ZJ-2216), Cyrus Tang Foundation for Young Scholar 2022 (2022-B126) and Sino-German Mobility Programme (M-0015).

Geneenvironment interaction between phthalate exposure and pubertal genetic polymorphisms on blood pressure variability in children: Exploring the moderating effects of lifestyle behaviours.

Phthalates (PAEs) are synthetic compounds extensively employed in consumer products. Blood pressure (BP) in children can vary, the degree of visit-to-visit BP variability (VVV) is at least partially independent of BP. The interactions between PAEs exposure, pubertal-related genetic susceptibility and lifestyles on childhood VVV are not investigated. This study utilized data from a cohort collected from Oct 2017-2020 in Xiamen, China. Seven urine PAE metabolites were measured. The long-term VVV was characterized employing the standard deviation (SD) and average real variability. We constructed a genetic risk score (GRS) of pubertal-related genes and healthy lifestyle scores. Exposed to high levels of mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) (OR=1.43, 95 %CI=1.07, 1.92) and mono-2-ethyl-5-oxohexyl phthalate (OR=1.36, 95 % CI=1.01, 1.83) was related to increased SBP-SD, and the OR for high SBP-SD related to high GRS was 1.38 (95 % CI=1.02, 1.85). Compared to participants who had low GRS and low MEHHP exposure, participants exhibiting high GRS and MEHHP levels were more likely to experience high SBP-SD (OR=2.00, P<0.05). Individuals exhibiting low GRS, low MEHHP levels, and adhering to healthy lifestyles were associated with the least probability of experiencing high SBP-SD (OR=0.31, P<0.05). Increased PAEs exposure could elevate childhood systolic VVV, and exacerbated the adverse impact of pubertal-related genetic susceptibility on the high VVV of SBP; however, healthy lifestyles might alleviate these adverse effects. Promoting healthy lifestyles and reducing PAEs exposure for preventing elevated BP variability among children is important, especially for individuals with greater genetic susceptibility to early pubertal onset. ENVIRONMENTAL IMPLICATION: Blood pressure (BP) in children can vary, as a noninvasive, inexpensive and applicable method, the extent of visit-to-visit variability (VVV) is at least partially independent of BP. The interactions between phthalates (PAEs) exposure, variants of puberty-related genes and lifestyles on VVV are not investigated. Increased childhood systolic VVV might be associated with PAEs exposure, with the associations more pronounced combined with pubertal genetic susceptibility. Yet, healthy habits could partly eliminate such adverse effects. Our study underscores the importance of advocating for healthy lifestyles and reducing exposure to PAEs, especially among individuals with high genetic susceptibility to early puberty onset.

A cluster randomized trial of a comprehensive intervention nesting family and clinic into school centered implementation to reduce myopia and obesity among children and adolescents in Beijing, China: study protocol.

BACKGROUND: Myopia and obesity in children and adolescents have become serious public health problems that endanger public health, especially in China. Unhealthy lifestyle behaviors are environmental drivers of both myopia and obesity. This protocol describes a study to evaluate the effectiveness of "22510SS", that is 2 h of daytime outdoor activities ('2'); Limit screen time to no more than 2 h per day ('2'); Consume at least 5 servings of fruits and vegetables daily ('5'); Attain 1 h of physical activity daily ('1'); Consume 0 sugar-sweetened beverages ('0'); Reasonable sleep duration ('S'); Regular supervision ('S'). A school-based, multifaceted intervention strategy for myopia and obesity prevention, and to assess and explore the implementation of "22510SS" with regards to acceptability, feasibility, adoption, usage and maintenance. METHODS AND ANALYSIS: This study aims to develop a comprehensive intervention strategy "22510SS" based on the socio-ecological model, and A two-arm cluster randomized trial with a parallel-group of a 1:1 allocation ratio in 36 primary and secondary schools to test its evidence-based intervention programs on the effects and implementation of myopia and obesity epidemics in children and adolescents in grades 4 and 7. The primary outcomes will include differences in visual acuity, body mass index, outdoor activity indicators, screen time, fruit and vegetable intake, high-quality protein intake, sugar-sweetened beverage intake, sleep duration, and level of monitoring among children and adolescents. Secondary outcomes will assess the acceptability, feasibility, uptake, use, and maintenance of the intervention. Effects on the primary and secondary outcomes will be analyzed using linear and logistic regression analyses, as well as difference-in-difference analysis, taking into account cluster effects and possible confounding factors. Process assessments will also be conducted through quantitative and qualitative analyses, including acceptability, feasibility, gender, adoption, implementation, and sustainability. DISCUSSION: This study will evaluate the effectiveness of "22510SS" and examine its implementation in the school-based network nesting family and clinic. Following this intervention study, the integrated intervention program focused on myopia and obesity among children and adolescents have great potential to be implemented in China to promote and support healthy lifestyle behavior change and reduce the risk of myopia and obesity in children and adolescents. TRIAL REGISTRATION: NCT05275959. Registered 23 Mach 2022.

Associations between genetic variants of HSD17B13 and fasting plasma glucose in Chinese children.

BACKGROUND AND AIMS: Genetic variants in 17-ß hydroxysteroid dehydrogenase 13 (HSD17B13) were demonstrated to protect against NAFLD, which is highly related with insulin resistance and dyslipidemia. However, the effects of NAFLD associated HSD17B13 variants on circulating glucose and lipids have not been adequately investigated in children. This study aimed to investigate associations between single nucleotide polymorphisms (SNPs) of HSD17B13 and NAFLD or its related phenotypes, such as blood glucose and serum lipids in Chinese children. METHODS AND RESULTS: We studied 1027 Chinese Han children aged 7-18 years old, which included 162 NAFLD children and 865 controls without NAFLD. Three SNPs (rs13112695, rs7692397, rs6834314) in HSD17B13 were genotyped. The multivariable logistic and linear regression models were applied to detect the associations between three SNPs and NAFLD or its related phenotypes [alanine transaminase (ALT), fasting plasma glucose (FPG) and serum lipids]. The effect allele A of rs7692397 was negatively associated with FPG [ß (SE) = -0.088 (0.027) mmol/L, P = 0.001], whereas the effect allele G of rs6834314 was positively associated with FPG (ß (SE) = 0.060 (0.019) mmol/L, P = 0.002). After Bonferroni correction, the significant associations still remained (both P < 0.0024). No significant associations were found for NAFLD or serum lipids. CONCLUSION: The study firstly revealed the association between two HSD17B13 variants and FPG in Chinese children, providing evidence for HSD17B13 variants and abnormal glucose metabolism.

The effect of rs 12145833 polymorphism of SDCCAG 8 gene on intervention of childhood obesity / 中国学校卫生

Objective@#To study the role of rs 12145833 polymorphism of SDCCAG 8 gene in the intervention of childhood obesity, so as to provide scientific basis for formulating personalized intervention measures based on genetic background in children with obesity.@*Methods@#From September 2018 to June 2019, a total of 393 children aged 8-10 years in Beijing were enrolled in a cluster randomized controlled trial. Eight schools were randomly allocated into intervention group and control group at a ratio of 1∶1. Saliva DNA samples were collected to detect rs 12145833 polymorphism of SDCCAG 8 gene. The intervention group received a comprehensive intervention, while the control group received usual practice. Intervention measures included diet improvement, sports, school amd family sport. The obesity related indicators were measured at baseline and after the end of intervention 1 academic year. Multiple linear regression and Logistic regression were used to analyze the interaction between genes and intervention on obesity indicators.@*Results@#In the intervention group, children with TT genotype of rs 12145833 of the SDCCAG 8 gene had less increase in systolic( β=4.56, 95%CI=1.84-7.28, P <0.01) and diastolic blood pressure( β=2.59, 95%CI=0.45-4.73, P <0.05) than those with GT and GG genotypes. In the control group, the systolic blood pressure of children with TT genotype increased more than those with GT and GG genotype( β=-2.86, 95%CI=-5.63--0.83, P <0.05). There was an interaction between rs 12145833 polymorphism of SDCCAG 8 gene and intervention on systolic blood pressure, diastolic blood pressure and body fat percentage in children( P <0.05).@*Conclusion@#Children with TT genotype of rs 12145833 in the SDCCAG 8 gene are more sensitive to obesity intervention than those with GG and GT genotypes, especially in the improvement of systolic blood pressure, diastolic blood pressure and body fat percentage. Further trials to study the role of rs 12145833 polymorphism of SDCCAG 8 gene in the intervention of childhood obesity among different ethnic populations are needed.

Maternal DHA-rich n-3 PUFAs supplementation interacts with FADS genotypes to influence the profiles of PUFAs in the colostrum among Chinese Han population: a birth cohort study.

BACKGROUND: The single nucleotide polymorphisms (SNPs) in the fatty acid desaturases and elongases might associate with the endogenous synthesis of polyunsaturated fatty acids (PUFAs). However, the related epidemiological evidence is still conflicting. So we aimed to clearly evaluate the interactions between maternal DHA-rich n-3 PUFAs supplementation and the known 26 SNPs on the profiles of PUFAs in the colostrum using a Chinese birth cohort. METHODS: Totally, 1050 healthy mother-infant pairs were enrolled in this study at gestational 6-8 weeks when they established their pregnancy files at Fuxing Hospital affiliated to Capital Medical University in Beijing from January to December 2018. Meanwhile, their venous blood samples were obtained for DNA extraction to detect the genotypes of SNPs in the Fads1, Fads2, Fads3, Elovl2 and Elovl5 using the Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry. Then the colostrum samples were collected to determine the profiles of PUFAs by gas chromatography. RESULTS: Maternal DHA-rich n-3 PUFAs supplementation from the early and middle pregnancy could reduce the infant BMI at birth, and impact the profiles of PUFAs in the colostrum, as higher n-3 PUFAs (EPA, DHA, DHA/ALA and DHA/EPA), lower n-6 PUFAs (AA and AA/LA) and ∑-6/n-3ΣPUFAs. Moreover, there were significant correlations between multiple SNPs and the profiles of n-6 PUFAs (rs76996928 for LA, rs174550, rs174553 and rs174609 for AA, rs174550 and rs76996928 for AA/LA) and n-3 PUFAs in the colostrum (rs174448, rs174537, rs174550, rs174553, rs174598, rs3168072, rs174455 and rs174464 for ALA, rs174550, rs174553 and rs174598 for EPA, rs174455 and rs174464 for DHA, rs174448 and rs3168072 for DHA/EPA) using the multiple linear regressions by adjusting the maternal age, gestational week, mode of delivery, infant sex and BMI at birth, and all these above significant SNPs had the cumulative effects on the profiles of PUFAs. Furthermore, the pairwise comparisons also showed the meaningful interactions between maternal DHA-rich n-3 PUFAs supplementation and related genotypes of SNPs (rs76996928 for LA, rs174598 for EPA, rs174448 for DHA and DHA/EPA) on the contents of PUFAs in the colostrum. CONCLUSIONS: Results from this birth cohort study proved that the pregnant women with the following SNPs such as Fads3 rs174455 T, Fads3 rs174464 A and Fads1 rs174448 G alleles should pay more attention on their exogenous DHA supplementation from the early and middle pregnancy for the blocked endogenous synthesis. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Beijing Pediatric Research Institution, Beijing Children's Hospital affiliated to Capital Medical University (2016-08), which was also registered at the website of http://www.chictr.org.cn/showproj.aspx?proj=4673 (No: ChiCTR-OCH-14004900).

Fine Mapping of the MAP2K5 Region Identified rs7175517 as a Causal Variant Related to BMI in China and the United Kingdom Populations.

Background: Genome-wide association studies (GWASs) have consistently identified MAP2K5 as an obesity susceptibility gene. To deepen our understanding of the potential causal genetic variants of this region, a fine-mapping study of MAP2K5 was conducted. Methods and Results: SNPs rs7175517 (G > A) and rs4776970 (T > A) were identified as the leading SNPs associated with BMI in both Chinese and the United Kingdom populations. Second, colocalization of GWAS and expression quantitative trait loci (eQTL) analyses and bioinformatic analyses indicated that rs7175517 is the functionally leading variant in the MAP2K5 gene region. Dual-luciferase assays indicated that the G allele of rs7175517 reduced the mRNA expression of MAP2K5 in HEK293T cells. The possible mechanism was that the G allele interacted with more RNA repressors from nuclei extracts, which was evidenced by electrophoretic mobility shift assays (EMSAs). Furthermore, the pathway enrichment analyses of the products from DNA pull-down and protein mass spectrometry demonstrated that the G allele of rs7175517 might interact with RNA catabolic or splicing transcription factors, which consequentially increased adiposity deposition. Conclusion: SNP rs7175517 of the MAP2K5 gene was the putative causal variant associated with BMI. More precisely designed in vitro or animal experiments are warranted to further delineate the function of MAP2K5 in adipogenesis.

Associations of genetic variants of lysophosphatidylcholine metabolic enzymes with levels of serum lipids.

OBJECTIVE: Metabolic disturbance of lysophosphatidylcholine (LPC) is related with dyslipidemia. Therefore, eight single-nucleotide polymorphisms (SNPs) were selected from LPC metabolic enzymes to study their associations with obesity and serum levels of lipids. METHODS: A total of 3305 children were recruited from four independent studies. Eight SNPs of LPC metabolic enzymes were selected and genotyped with the matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). The multivariable linear regression model was applied to detect the associations of eight SNPs with obesity-related phenotypes and levels of lipids in each study. Meta-analyses were used to combine the results of four studies. RESULTS: Only SNP rs4420638 of APOC-1 gene was associated with serum lipids even after Bonferroni correction. The rs4420638 was positively associated with TC (ß = 0.15, P = 8.59 × 10-9) and low-density-lipoprotein-cholesterol (LDL-C, ß = 0.16, P = 9.98 × 10-14) individually. CONCLUSION: The study firstly revealed the association between APOC-1/rs4420638 and levels of serum lipids in Chinese children, providing evidence for susceptible gene variants of dyslipidemia.

Genetic variants in the FAM3C gene are associated with lipid traits in Chinese children.

BACKGROUND: Previous studies have related FAM3C gene with childhood bone health, and the regulation of lipid metabolism in hepatocytes. The present case-control study aimed to analyze the association of FAM3C genetic variants with overweight/obesity and lipid traits among Chinese children. METHODS: Two genetic variants (rs7776725 and rs7793554) within the FAM3C gene were genotyped in 3305 Chinese children aged 6-18 years. RESULTS: In the whole study population, the T-allele of rs7776725 and A-allele of rs7793554 within the FAM3C gene were associated with 40.2% (95% CI: 11.6-76.1%; P = 0.004) and 29.1% (6.9-56.0%; P = 0.008) increased risk of dyslipidemia, higher triglyceride (P = 0.014 and P = 0.001) and lower HDL-C (P = 0.015 and P = 0.003). In addition, we found that rs7776725 interacted with sex on dyslipidemia (Pfor interaction = 0.004), and sex-stratified analyses showed that it was significantly associated with dyslipidemia only in girls (P = 8.78 × 10-5). The variant also showed nominally significant interactions with sex on total cholesterol and LDL-C (Pfor interaction = 0.012 and 0.008). CONCLUSION: We found that FAM3C genetic variants were associated with dyslipidemia and lipid traits among Chinese children. In addition, we found significant gene-by-sex interactions. Our findings provided evidence supporting the role of FAM3C gene in regulating lipid metabolism in humans. IMPACT: FAM3C genetic variants were associated with dyslipidemia and lipid traits among Chinese children. In addition, we found significant gene-by-sex interactions. FAM3C/rs7776725 was associated with dyslipidemia and lipid traits only in girls. Our findings provided evidence supporting the role of FAM3C gene in regulating lipid metabolism in humans.

The association of the glucokinase rs4607517 polymorphism with gestational diabetes mellitus and its interaction with sweets consumption in Chinese women.

OBJECTIVE: To identify the association of the glucokinase gene (GCK) rs4607517 polymorphism with gestational diabetes mellitus (GDM) and determine whether sweets consumption could interact with the polymorphism on GDM in Chinese women. DESIGN: We conducted a case-control study at a hospital including 1015 participants (562 GDM cases and 453 controls). We collected the data of pre-pregnancy BMI, sweets consumption and performed genotyping of the GCK rs4607517 polymorphism. Logistic regression was performed to test the association between the rs4607517 polymorphism and GDM, and the stratified analyses by sweets consumption were conducted, using an additive genetic model. SETTING: A case-control study of women at a hospital in Beijing, China. PARTICIPANTS: One thousand and fifteen Chinese women. RESULTS: The GCK rs4607517 A allele was significantly associated with GDM (OR 1·35, 95 % CI 1·03, 1·77; P = 0·028). Furthermore, stratified analyses showed that the A allele increased the risk of GDM only in women who had a habitual consumption of sweet foods (sweets consumption ≥ once per week) (OR 1·61, 95 % CI 1·17, 2·21; P = 0·003). Significant interaction on GDM was found between the rs4607517 A allele and sweets consumption (P = 0·004). CONCLUSIONS: This study for the first time reported the interaction between the GCK rs4607517 polymorphism and sweets consumption on GDM. The results provided novel evidence for risk assessment and personalised prevention of GDM.

Association study between single nucleotide polymorphisms of UGT1A1 with NAFLD and serum lipids in children / 中国学校卫生

Objective@#To investigate the associations between single nucleotide polymorphisms of UDP glucuronosyltransferase Family 1 Member A1 ( UGT1A1 ) with non alcoholic fatty liver disease (NAFLD) and levels of serum lipids in Beijing children, and to provide scientific evidence for the study of genetic mechanism.@*Methods@#In total, 1 027 children aged 7-18 years were recruited from two primary schools and three middle schools from Haidian district of Beijing, who were randomly assigned to case group ( n =162) and control group ( n =865). General condition and medical history were collected by trained field health workers. Height, weight and liver ultrasound were examined. Additionally, fasting venous blood were collected to detect serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and alanine aminotransferase (ALT). The single nucleotide polymorphisms (SNPs) of UGT1A1 were genotyped. Binary logistic regression and multiple linear regression were applied to analyze the associations between three SNPs of UGT1A1 and NAFLD, ALT and levels of serum lipids.@*Results@#The SNP rs 10929303 (C>T) of UGT1A1 was negatively associated with NAFLD( OR=0.51, 95%CI=0.32- 0.83 , P =0.01), while the SNP rs 4148323 (G>A) was negatively associated with the serum level of TC ( B=-0.10, 95%CI=-0.19- -0.02 , P =0.02); in addition, results were consistent regardless of whether the TC level was measured using a categorical variable or continuous variable.@*Conclusion@#The SNP rs 10929303 of UGT1A1 is associated with NAFLD, and the SNP rs 4148323 of UGT1A1 is associated with TC levels in Beijing children.

Causal associations of body mass index and waist-to-hip ratio with cardiometabolic traits among Chinese children: A Mendelian randomization study.

BACKGROUND AND AIMS: Body mass index (BMI) and waist-to-hip ratio (WHR) have been reported to be causally associated with cardiometabolic diseases in adults in European populations. However, this causality was less explored in East Asian populations and in children. Our study aimed to explore and compare the causal associations of general obesity (measured by BMI) and central obesity (measured by WHR) with cardiometabolic traits. METHODS AND RESULTS: We performed a Mendelian randomization (MR) analysis in 2030 unrelated children from two independent case-control studies in Beijing, China. BMI-associated single nucleotide polymorphisms (SNPs) and WHR-SNPs identified by previous genome-wide association studies were used as genetic instruments to examine the casual associations of BMI and WHR with cardiometabolic traits, including glycemic traits, blood lipids, and blood pressure. Each 1-SD increase in BMI and WHR were significantly associated with 0.111 mmol/L and 0.110 mmol/L increase in log-transformed fasting insulin (FINS), 0.049 and 0.060 increase in log-transformed HOMA-ß, 0.112 and 0.108 increase in log-transformed HOMA-IR, 0.009 mmol/L and 0.015 mmol/L increase in log-transformed triglyceride, and 15.527 mmHg and 7.277 mmHg increase in systolic blood pressure, respectively (all P < 0.05). The receiver operating characteristic curves showed that WHR had a stronger effect on FINS, HOMA-ß, HOMA-IR, and triglyceride than BMI (all P < 0.05). CONCLUSIONS: Using the MR method, we found that the genetic predisposition to higher BMI or WHR was associated with altered cardiometabolic traits in Chinese children. When compared with general obesity, central obesity might have stronger effects on glycemic traits and blood lipids among children.

DNA methylation of the INSR gene as a mediator of the association between prenatal exposure to famine and adulthood waist circumference.

The aims of this study were to explore whether DNA methylation at INSR and IGF2 mediated the association of prenatal exposure to the Chinese great famine with adulthood waist circumference (WC) and BMI. A total of 235 subjects were selected into the present study from severely affected province and a neighbor province with less severely affected famine in China through multi-stage clustered random sampling. DNA methylation at the INSR and IGF2 gene promoter regions was detected by the Sequenom's MassARRAY system. The "mediation" package of R was used to evaluate the mediation effect of DNA methylation on the association between prenatal exposure to the famine and adult WC and BMI. The results showed that prenatal famine exposure was significantly associated with higher overall methylation level of the INSR gene (d = 3.6%; 95% CI 1.2-6.0; P = 0.027) and larger adulthood WC (d = 2.72 cm; 95% CI 0.20-5.24; P = 0.034). Furthermore, famine significantly increased methylation levels at four CpG sites. Methylation of the CpG7 site mediated 32.0% (95% CI 5.0-100.0%, P = 0.029) of the association between prenatal exposure to the Chinese great famine and adulthood WC. In conclusion, Epigenetic changes to the INSR might mediate the adverse effect of prenatal famine exposure on WC in adulthood.

Correction: Genetic variations in sterol regulatory element binding protein cleavage-activating protein (SCAP) are associated with blood pressure in overweight/obese Chinese children.

[This corrects the article DOI: 10.1371/journal.pone.0177973.].

Physical activity attenuates the association between the IRS1 genotype and childhood obesity in Chinese children.

BACKGROUND AND AIMS: The insulin receptor substrate 1 (IRS1) rs2943650 was found to be associated with obesity in adults, but the association has not been evaluated in children. The present study aimed to examine whether IRS1 rs2943650 was associated with obesity in Chinese children and investigate the interaction between rs2943650 and physical activity. METHODS AND RESULTS: IRS1 rs2943650 was genotyped in 3303 Chinese children aged 6-18 years recruited from four independent studies. Logistic regression and linear regression were performed to examine associations. Meta-analyses were conducted to pool the results of the four independent studies. The C-allele carriers of rs2943650 showed a 29% higher risk of obesity than noncarriers (OR (95% CI) = 1.29 (1.05, 1.58), P = 0.02) and a 0.41 kg/m2 increase in BMI (ß (95% CI) = 0.41 (0.05, 0.78) kg/m2, P = 0.02). We also observed significant interactions between rs2943650 and physical activity/sedentary behaviors on obesity (Pforinteraction<0.05). Compared with the physically active children (physical activity ≥1 h/d and sedentary behaviors <2 h/d), the risk allele (C) of rs2943650 was significantly associated with a 241% increased risk of obesity among inactive children who participated in physical activity <1 h/d and sedentary behaviors ≥2 h/d (OR (95% CI) = 3.41 (1.45, 8.01), P = 0.005). CONCLUSIONS: We found that IRS1 rs2943650 was significantly associated with BMI and risk of childhood obesity. Additionally, we also found significant interaction between IRS1 rs2943650 polymorphism and physical activity/sedentary behaviors on childhood obesity. Our study would provide novel insights into the function of the IRS1 gene and the implementation of effective intervention strategies of childhood obesity.

Combined effects of the rs9810888 polymorphism in calcium voltage-gated channel subunit alpha1 D (CACNA1D) and lifestyle behaviors on blood pressure level among Chinese children.

BACKGROUNDS: A recent GWAS Study found a new locus (rs9810888 in CACNA1D) was associated with blood pressure (BP) in Chinese adults. But whether the association exists in children is unknown. Whether lifestyle behaviors could interact with rs9810888 on BP is not clear. This study aimed to identify the association between rs9810888 and BP in children, and also explore the gene-lifestyle interaction. METHODS: A case-control study was conducted among 2030 Chinese children aged 7 to 18 years. Genotyping was conducted by using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Lifestyle behaviors were investigated with questionnaire. RESULTS: With adjustment for age, age square, sex, study group and body mass index (BMI), rs9810888 was significantly associated with diastolic BP (DBP) (b = 1.69, p = 0.021) and mean arterial BP (MAP) (b = 1.56, p = 0.010). Stratified analysis showed that the rs9810888 GG genotype carriers had higher DBP than GT/TT carriers (b = 3.78, p = 0.023) in the subgroup having protein intake (meat/fish/soybeans/egg)

Interaction between lifestyle behaviors and genetic polymorphism in SCAP gene on blood pressure among Chinese children.

BACKGROUNDS: Previous studies had revealed that sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) rs12487736 polymorphism was associated with blood pressure (BP), but whether rs12487736 could interact with lifestyle behaviors on BP is unknown. METHODS: A case-control study with 1092 Chinese children was conducted. RESULTS: We found an interaction between rs12487736 and high calorie foods intake (fried chips/cakes/cookies) on systolic blood pressure (SBP) (Pinteraction = 0.027), and rs12487736 was associated with SBP in the subgroup having high calorie foods at least once in the last week (b = 2.19, P = 0.025), but not in the subgroup not having high calorie foods. Also, interaction between protein intake (meat/fish/soy beans/egg) and rs12487736 on diastolic BP (DBP) was identified (Pinteraction = 0.049); rs12487736 was associated with DBP in the subgroup consuming protein (meat/fish/soy beans/egg)

Early-Life Exposure to the Chinese Famine Is Associated with Higher Methylation Level in the INSR Gene in Later Adulthood.

We examined the association between the China famine exposure in early life and DNA methylation of INSR (hg18, chr19:7110130-7110574) and CPT1A (hg18, chr11: 68286513-68286952) related to growth and metabolism in 235 subjects selected from two provinces in China. The subjects were categorized into prenatal famine-exposed group and non-exposed group based on their birthdates. DNA methylation at the INSR gene locus was assayed from peripheral white blood cells using the Sequenom's MassARRAY system. Two dependent samples t-test was used to compare the difference between the exposed group and non-exposed group. DNA methylation level of INSR was higher among individuals who exposed to the China famine in the fetus than that of non-exposed group (d = 3.3%, P = 0.006). A significant interaction between famine exposure and province was observed for INSR (Pinteraction < 0.001). DNA methylation level of INSR was positively associated with triglyceride (ß = 0.011, P = 0.021), and negatively associated with high-density lipoprotein cholesterol (ß = -0.039, P = 0.021). Moreover, exposed group had higher meat consumption than non-exposed group in severe exposure area. Prenatal exposure to the China famine plus later life eating habits might regulate epigenome.

Lipidomic Profile Revealed the Association of Plasma Lysophosphatidylcholines with Adolescent Obesity.

OBJECTIVE: The human lipidomic profile reflects lipid metabolism, including the early phase of pathophysiological changes associated with diseases. An investigation of the association between the plasma lipidomic profile and adolescent obesity might provide new insights into the biological mechanisms of obesity. Therefore, we aimed to investigate the association of the plasma lipidome with obesity in Chinese adolescents using lipidomics. METHODS: Using a combination of liquid chromatography and electrospray ionization tandem mass spectrometry, we quantified 328 lipid species from 24 lipid classes and subclasses in 100 male adolescents aged 14-16 years who were categorized into four groups: (1) normal weight with traditional normal clinical plasma lipid levels (NN); (2) normal weight with traditional abnormal clinical plasma lipid levels (NA); (3) obese with traditional normal clinical plasma lipid levels (ON); and (4) obese with traditional abnormal clinical plasma lipid levels (OA). The concentrations of all the lipid species were compared between obese and normal-weight adolescents at different traditional clinical plasma lipid levels using the Kruskal-Wallis test followed by the Mann-Whitney U test. A partial least squares discriminant analysis (PLS-DA) was applied to select lipids with a significant ability to discriminate adolescent obesity. RESULTS: The lipidomic profile distinguished obese adolescents from normal-weight subjects. Regardless of whether traditional clinical plasma lipid levels were normal or abnormal, we observed a significant reduction in the levels of five lysophosphatidylcholines (LPC) species (LPC18:2, LPC18:1, LPC20:2, LPC20:1, and LPC20:0) in the obese group compared with the normal-weight group (difference = -31.29% to -13.19%; P=9.91 × 10-5 to 2.28 × 10-2). The ability of these five LPC species to discriminate adolescent obesity was confirmed in the PLS-DA model. CONCLUSIONS: The findings provided evidence for the association of some LPC species with adolescent obesity. The discriminatory effects of five LPC species were identified between normal-weight and obese adolescents, independent of traditional clinical plasma lipid levels. These results will provide a basis for validation in subsequent studies.