Meixian Zhang

The common rs9939609 variant of the fat mass and obesity-associated gene is associated with obesity risk in children and adolescents of Beijing, China

BackgroundPrevious genome-wide association studies for type 2 diabetes susceptibility genes have confirmed that a common variant, rs9939609, in the fat mass and obesity associated (FTO) gene region is associated with body mass index (BMI) in European children and adults. A significant association of the same risk allele has been described in Asian adult populations, but the results are conflicting. In addition, no replication studies have been conducted in children and adolescents of Asian ancestry.MethodsA population-based survey was carried out among 3503 children and adolescents (6-18 years of age) in Beijing, China, including 1229 obese and 2274 non-obese subjects. We investigated the association of rs9939609 with BMI and the risk of obesity. In addition, we tested the association of rs9939609 with weight, height, waist circumference, waist-to-height ratio, fat mass percentage, birth weight, blood pressure and related metabolic traits.ResultsWe found significant associations of rs9939609 variant with weight, BMI, BMI standard deviation score (BMI-SDS), waist circumference, waist-to-height ratio, and fat mass percentage in children and adolescents (p for trend = 3.29 × 10-5, 1.39 × 10-6, 3.76 × 10-6, 2.26 × 10-5, 1.94 × 10-5, and 9.75 × 10-5, respectively). No significant associations were detected with height, birth weight, systolic and diastolic blood pressure and related metabolic traits such as total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol and fasting plasma glucose (all p > 0.05). Each additional copy of the rs9939609 A allele was associated with a BMI increase of 0.79 [95% Confidence interval (CI) 0.47 to 1.10] kg/m2, equivalent to 0.25 (95%CI 0.14 to 0.35) BMI-SDS units. This rs9939609 variant is significantly associated with the risk of obesity under an additive model [Odds ratio (OR) = 1.29, 95% CI 1.11 to 1.50] after adjusting for age and gender. Moreover, an interaction between the FTO rs9939609 genotype and physical activity (p < 0.001) was detected on BMI levels, the effect of rs9939609-A allele on BMI being (0.95 ± 0.10), (0.77 ± 0.08) and (0.67 ± 0.05) kg/m2, for subjects who performed low, moderate and severe intensity physical activity.ConclusionThe FTO rs9939609 variant is strongly associated with BMI and the risk of obesity in a population of children and adolescents in Beijing, China.

Associations of Six Single Nucleotide Polymorphisms in Obesity-Related Genes With BMI and Risk of Obesity in Chinese Children

OBJECTIVE Childhood obesity strongly predisposes to some adult diseases. Recently, genome-wide association (GWA) studies in Caucasians identified multiple single nucleotide polymorphisms (SNPs) associated with BMI and obesity. The associations of those SNPs with BMI and obesity among other ethnicities are not fully described, especially in children. Among those previously identified SNPs, we selected six (rs7138803, rs1805081, rs6499640, rs17782313, rs6265, and rs10938397, in or near obesity-related genes FAIM2, NPC1, FTO, MC4R, BDNF, and GNPDA2, respectively) because of the relatively high minor allele frequencies in Chinese individuals and tested the associations of the SNPs with BMI and obesity in Chinese children. RESEARCH DESIGN AND METHODS We investigated the associations of these SNPs with BMI and obesity in school-aged children. A total of 3,503 children participated in the study, including 1,229 obese, 655 overweight, and 1,619 normal-weight children (diagnosed by the Chinese age- and sex-specific BMI cutoffs). RESULTS After age and sex adjustment and correction for multiple testing, the SNPs rs17782313, rs6265, and rs10938397 were associated with BMI (P = 1.0 × 10−5, 0.038, and 0.00093, respectively) and also obesity (P = 5.0 × 10−6, 0.043, and 0.00085, respectively) in the Chinese children. The SNPs rs17782313 and rs10938397 were also significantly associated with waist circumference, waist-to-height ratio, and fat mass percentage. CONCLUSIONS Results of this study support obesity-related genes in adults as important genes for BMI variation in children and suggest that some SNPs identified by GWA studies in Caucasians also confer risk for obesity in Chinese children.

Adiponectin and Leptin Metabolic Biomarkers in Chinese Children and Adolescents

Objective. To evaluate leptin and adiponectin as biomarkers of metabolic syndrome (MS) risk factors even in nonobese children/adolescents. Methods. Serum leptin, adiponectin, leptin:adiponectin ratio, lipids, glucose, and insulin concentrations as well as body size parameters and pubertal development were evaluated in a large population of Chinese children/adolescents (n = 3505, 6–18 years, 1722 girls and 1783 boys). Results. Leptin concentration increased while adiponectin decreased with obesity, both were influenced by pubertal development. Central obesity had an additive effect on leptin levels (above obesity alone). Leptin/adiponectin increased 8.4-fold and 3.2-fold in overweight/obesity, and 15.8- and 4.5-fold with obesity plus MS, in early and late puberty, respectively. Even in normal weight children/adolescents, higher leptin and lower adiponectin concentrations associated with increased risk profile. Conversely, overweight/obese with lower leptin or higher adiponectin concentrations had a less compromised metabolic profile. Conclusion. Leptin, adiponectin, and leptin:adiponectin ratio are informative biomarkers for obesity, central obesity, MS, and abnormal metabolic profile even in normal weight children/adolescents.

Acylation stimulating protein but not complement C3 associates with metabolic syndrome components in Chinese children and adolescents

OBJECTIVE Childhood obesity is increasing worldwide and is increasingly associated with metabolic syndrome (MetS). Our aim was to examine acylation stimulating protein (ASP) and its precursor complement C3, in normal, overweight, and obese Chinese children and adolescents, and the relationships with body size, blood parameters, pubertal development, family environment, and MetS. METHODS Children and adolescents (n=1603) from 6 to 18 years, boys (n=873) and girls (n=730), including normal weight (n=603), overweight (n=291) and obese (n=709) were assessed for body size parameters, pubertal development, blood lipids, glucose, insulin, ASP, and C3. RESULTS ASP levels were increased in overweight and obese versus normal weight (P<0.001), while C3 showed little variation. This effect of overweight/obesity remained throughout early stages when boys and girls were separated by pubertal development or age, although age and pubertal status itself had no effect. Separation based on ASP quintiles demonstrated significant associations with blood cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-Chol), glucose, insulin, and homeostatic model assessment of insulin resistance in boys, and LDL-Chol, high-density lipoprotein cholesterol, and glucose in girls. A positive correlation with mothers body mass index in boys and girls (P=0.002 and P=0.014 respectively) as well as birth weight (P<0.001) was noted. MetS was strongly associated with increased ASP, the presence of a single MetS factor (especially hypertension, central obesity, or hyperglycemia) was associated with increased ASP. CONCLUSION Changes in the plasma adipokine ASP in early obesity are associated with blood lipid and glucose modifications, family environment, and distinct MetS risk factors.

Age- and sex-dependent association between FTO rs9939609 and obesity-related traits in Chinese children and adolescents.

Background The associations between common variants in the fat mass- and obesity-associated (FTO) gene and obesity-related traits may be age-dependent and may differ by sex. The present study aimed to assess the association of FTO rs9939609 with body mass index (BMI) and the risk of obesity from childhood to adolescence, and to determine the age at which the association becomes evident. Methods Totally 757 obese and 2,746 non-obese Chinese children aged 6–18 years were genotyped for FTO rs9939609. Of these, a young sub-cohort (n = 777) aged 6–11 years was reexamined 6 years later. Obesity was defined using the sex- and age-specific BMI cut-offs recommended by the International Obesity Task Force. Results The associations of FTO rs9939609 with BMI and obesity did not appear until children reached 12–14 years. The variant was associated with an increased BMI in boys (β = 1.50, P = 0.004) and girls (β = 0.97, P = 0.018), respectively. Thereafter, the magnitude of association increased in girls at ages 15–18 years (β = 2.02, P<0.001), but not boys (β = 0.10, P>0.05). Age was found to interact with the variant on BMI (P<0.001) and obesity (P = 0.042) only in girls. In the sub-cohort, the associations of FTO rs9939609 with BMI (β = 1.07, P = 0.008) and obesity (OR = 2.09, 95% CI: 1.12, 3.91) were only observed 6 years later (ages 12–18 years) in girls, even after adjusting for baseline BMI. Conclusions The association between FTO rs9939609 and obesity-related traits may change from childhood to adolescence in Chinese individuals, and the association may start as early as age 12 years, especially in girls.

Promoter methylation of fas apoptotic inhibitory molecule 2 gene is associated with obesity and dyslipidaemia in Chinese children

Fas apoptotic inhibitory molecule 2 (FAIM2) is an obesity-related gene, but the mechanisms by which FAIM2 is involved in obesity are not understood. Epigenetic alterations are important factors in the development of obesity. The purpose of this study was to investigate the potential associations of FAIM2 promoter methylation with obesity and components of dyslipidaemia in Chinese children. We studied FAIM2 promoter methylation in 59 obese and 39 lean children using the Sequenom MassARRAY platform. The methylation levels at 8 CpG sites in the FAIM2 promoter were significantly different between the obese and lean subjects, especially the methylation level at CpG site 500 (p = 0.01). The methylation levels at several of the examined CpG sites were significantly associated with dyslipidaemia and its components after adjusting for age, gender and body mass index (BMI). The methylation levels at two CpG sites (sites -362 and -360 and site -164) were highly significantly associated with high level of triglycerides (p = 0.00002 and 0.0009, respectively). This study provides the first evidence that the methylation levels of the FAIM2 promoter are significantly associated with obesity and are independently associated with dyslipidaemia and its components in Chinese children.

Influence of lifestyle on the FAIM2 promoter methylation between obese and lean children: a cohort study

Objective An obesity-related gene, Fas apoptotic inhibitory molecule 2 (FAIM2), is regulated by nutritional state and the methylation levels of the FAIM2 promoter are significantly associated with obesity. Lifestyle factors, such as sedentary behaviour and physical activity, might modify epigenetic patterns that have been related to obesity. Whether the molecular mechanisms by which FAIM2 affects obesity are involved in lifestyle is unclear. This study investigates the potential differences of the FAIM2 promoter methylation with sedentary behaviour and physical activity in obese and lean children. Design Cohort study. Setting Institute of Pediatrics in China. Participants 59 obese cases and 39 lean controls aged 8–18 years recruited from a cross-sectional survey of children from Beijing in 2013. Primary and secondary outcome measures The FAIM2 promoter methylation was quantified using the Sequenom MassARRAY platform. Sedentary behaviour and physical activity were investigated using a questionnaire. The influences of different lifestyles on methylation variations in obese and lean children were examined by multiple linear regression. Results The methylation levels at seven CpG sites of the FAIM2 promoter were significantly associated with sedentary behaviour, especially the methylation levels at site −975, site −413, sites −362 and −360, and sites −353 and −349 (p=0.00004, 0.00009, 0.0006 and 0.00005, respectively). There were significant differences between the methylation levels at four CpG sites in obese and lean participants with high or moderate physical activity level <150 min/week. Conclusions This study provides the first evidence that there are significant differences in the associations of the FAIM2 promoter methylation with sedentary behaviour and physical activity between obese and lean children. Our results suggest that lifestyle may possibly be mediating the process of the FAIM2 involved in obesity.

Associations of Two Obesity-Related Single-Nucleotide Polymorphisms with Adiponectin in Chinese Children

Purpose. Genome-wide association studies have found two obesity-related single-nucleotide polymorphisms (SNPs), rs17782313 near the melanocortin-4 receptor (MC4R) gene and rs6265 near the brain-derived neurotrophic factor (BDNF) gene, but the associations of both SNPs with other obesity-related traits are not fully described, especially in children. The aim of the present study is to investigate the associations between the SNPs and adiponectin that has a regulatory role in glucose and lipid metabolism. Methods. We examined the associations of the SNPs with adiponectin in Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. A total of 3503 children participated in the study. Results. The SNP rs6265 was significantly associated with adiponectin under an additive model (P = 0.02 and 0.024, resp.) after adjustment for age, gender, and BMI or obesity statuses. The SNP rs17782313 was significantly associated with low adiponectin under a recessive model. No statistical significance was found between the two SNPs and low adiponectin after correction for multiple testing. Conclusion. We demonstrate for the first time that the SNP rs17782313 near MC4R and the SNP rs6265 near BDNF are associated with adiponectin in Chinese children. These novel findings provide important evidence that adiponectin possibly mediates MC4R and BDNF involved in obesity.

A new risk locus in CHCHD5 for hypertension and obesity in a Chinese child population: a cohort study

Objective Coiled-coil-helix-coiled-coil-helix domain containing 5 (CHCHD5), a mitochondrial protein, is involved in the oxidative folding process in the mitochondrial intermembrane space. A previous study identified a hypertension-related single nucleotide polymorphism (SNP), rs3748024, in CHCHD5 in adults, but there are no reports regarding the association between CHCHD5 and obesity, which is a known risk factor for hypertension. The aim of the present study is to investigate the associations of the SNP rs3748024 with hypertension and obesity. Design Cohort study. Setting Institute of Pediatrics in China. Participants We genotyped the SNP rs3748024 in the Beijing Child and Adolescent Metabolic Syndrome study. A total of 3503 children participated in the study. Primary and secondary outcome measures Genotyping of rs3748024 was conducted using the TaqMan Allelic Discrimination Assay. Lipids and glucose were analysed by an automatic biochemical analyser using a kit assay. The levels of adipocytokines (leptin, adiponectin and resistin) were measured by ELISA techniques. Results There was a statistically significant association between rs3748024 and systolic blood pressure (SBP) (β=−0.853, 95% CI −1.482 to −0.024, p=0.044) under an additive model adjusted for age, gender and body mass index (BMI) after correction for multiple testing. The SNP was also significantly associated with BMI (β=−0.286, 95% CI −0.551 to −0.021, p=0.043), obesity (OR=0.828, 95% CI 0.723 to 0.949, p=0.018) and triglycerides (β=−0.039, 95% CI −0.070 to −0.007, p=0.044) after correction for multiple testing. Conclusions We demonstrate for the first time that the SNP rs3748024 in CHCHD5 is associated with SBP, BMI, obesity and triglycerides in Chinese children. Our study identifies a new risk locus for hypertension and obesity in a child population. The function of CHCHD5 remains to be further studied to help elucidate the pathogenic role of CHCHD5 in hypertension and obesity.

Adipokines are Associated With Hypertension in Metabolically Healthy Obese (MHO) Children and Adolescents: A Prospective Population-Based Cohort Study

Background The potential mechanism underlying the relationship between the risk of cardiovascular diseases and metabolically healthy obese (MHO) individuals remains unclear. The aim of the study was to prospectively investigate the potential role of the adipokines in the association between the MHO phenotype and hypertension in children and adolescents. Methods A total of 1184 participants at baseline were recruited from a cohort of the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. The participants were classified according to their body mass index (BMI) and metabolic syndrome (MS) components. The levels of the adipokines, including leptin, adiponectin, and resistin, were measured. Results MHO individuals had higher leptin levels (11.58 ug/L vs 1.20 ug/L), leptin/adiponectin ratio (1.18 vs 0.07), and lower adiponectin (11.65 ug/L vs 15.64 ug/L) levels compared to metabolically healthy normal-weight individuals (all P < 0.05). Compared to metabolically healthy normal-weight individuals, the prevalence of high leptin levels (26.5% vs 0.4%), low adiponectin levels (17.9% vs 6.3%) and a high leptin/adiponectin ratio (26.0% vs 2.1%) was higher in MHO individuals (all P < 0.01). The MHO individuals with abnormal adipokines were significantly more likely to developing hypertension (high leptin, relative risk 11.04; 95% confidence interval, 1.18–103.35; and high leptin/adiponectin ratio, relative risk 9.88; 95% confidence interval, 1.11–87.97) compared to metabolically healthy normal-weight individuals with normal adipokine levels. Conclusions The abnormal adipokine levels contribute to the increased hypertension risk in MHO children and adolescents. The non-traditional risk factors should be highlighted in MHO children and adolescents in clinical practice and research.