GWAS-Identified Common Variants With Nonalcoholic Fatty Liver Disease in Chinese Children.

OBJECTIVES: Three genome-wide association studies were previously done for nonalcoholic fatty liver disease (NAFLD) among individuals of Western countries and identified several genetic variants associated with NAFLD. The study aimed to identify whether 7 GWAS-identified common variants (GCKR rs780094, PDGFA rs343064, FDFT1 rs2645424, COL13A1 rs1227756, EHBP1L1 rs6591182, NCAN rs2228603, and PNPLA3 rs738409) were associated with NAFLD in Chinese children. METHODS: This case-control study recruited 1027 Chinese children of age 7 to 18 years, including 162 children with NAFLD and 865 children without NAFLD. Anthropometric measurements, alanine transaminase (ALT) detection, liver ultrasound examination, and genotyping of 7 variants were performed. RESULTS: The G-allele of PNPLA3 rs738409 was associated with NAFLD (odds ratio [OR] 1.55, 95% confidence interval 1.13-2.11, P = 0.006) and moderate-to-severe steatosis (OR 3.77, 95% confidence interval 1.78-7.98, P = 0.001) adjusted for age, sex, and BMI standard deviation score. In addition, we found each G-allele of rs738409 increased ALT level by 1.09 IU/L (P = 0.011). Subjects carrying 10 or more risk alleles of 7 variants had an OR of 4.76 (P = 0.025) for NAFLD compared with subjects carrying 3 or fewer risk alleles. CONCLUSIONS: The PNPLA3 rs738409 G-allele was associated with NAFLD and ALT level in Chinese children. It had stronger association with moderate-to-severe steatosis. Children carrying 10 or more risk alleles of 7 variants were susceptible for NAFLD.

Association study of childhood obesity with eight genetic variants recently identified by genome-wide association studies.

BACKGROUND: Being overweight or obese is becoming increasingly common in low- and middle-income countries. The present study aimed to examine association of eight genetic variants with obesity and to estimate the cumulative effects of these variants in Chinese children. METHODS: We conducted the case-control study in a total of 2,030 subjects. Genotyping of seven novel variants was performed with matrix-assisted laser desorption ionization time of flight mass spectrometry, while rs9939609 was genotyped with tetra-primer amplification refractory mutation system analysis. RESULTS: The association of two fat mass and obesity-associated gene (FTO) single-nucleotide polymorphisms (SNPs; rs9939609 and rs62048402) with body mass index (BMI) or obesity reached nominal significance at P < 0.05. We found a cumulative effect of five SNPs on the risk of overweight and obesity (odds ratio (OR) = 1.197, 95% confidence interval (CI) = 1.068-1.342, P = 0.002). Subjects carrying 9 or more effect alleles had a 127% increased risk of overweight and obesity (OR = 2.270, 95% CI = 1.403-3.671, P = 0.001) compared with subjects who carry 6 or fewer effect alleles. CONCLUSION: We confirmed two FTO SNPs (rs62048402 and rs9939609) had nominal significant effects on BMI or obesity. We identified the cumulative effect of five SNPs on risk of overweight and obesity. The results provided evidence for identifying genetic factors related to childhood obesity.

Association of INSIG2 rs9308762 with ALT level independent of BMI.

OBJECTIVES: An increasing number of people are at risk for developing nonalcoholic fatty liver disease (NAFLD). Because obesity is a risk factor for NAFLD, the common variants of obesity-susceptible genes may be associated with NAFLD. Our aim was to identify whether the obesity-susceptible gene variants (rs9939609, rs9930506, and rs4783819 in fat mass and obesity-associated gene (FTO); rs12970134 and rs17782313 in melanocortin-4 receptor gene (MC4R); and rs7566605, rs13428113, and rs9308762 in insulin-induced gene 2 [INSIG2]) were associated with NAFLD. METHODS: The case-control study recruited 1027 Chinese children ages 7 to 18 years, including 162 children with NAFLD and 865 children without NAFLD. Anthropometric measurements, alanine transaminase (ALT) detection, liver ultrasound examination, and genotyping of 8 gene variants were performed. RESULTS: The A-allele of FTO rs9939609 was associated with increased NAFLD risk (P = 0.029, odds ratio  1.43), but was not significant after being adjusted for body mass index (BMI) (P = 0.268). We also found an association between the 2 variants (rs12970134 in MC4R and rs9308762 in INSIG2) and ALT level. For rs12970134, each additional A-allele increased ALT level by 1.87 IU/L (P = 0.032). For rs9308762, the homozygotes of the C-allele had a higher ALT level than the T-allele carriers (ß = 3.19, P = 0.007). After adjustment for BMI, the former association did not exist, whereas the latter reminded significant (P = 0.003). CONCLUSIONS: The FTO rs9939609 A-allele increased risk of NAFLD and MC4R rs12970134 was associated with ALT level through an effect on BMI. The association between INSIG2 rs9308762 and ALT level was independent of BMI. The results provided evidence for identifying genetic factors of NAFLD and may be useful for risk assessment and personalized medicine of NAFLD.

[Association of rs2228314 polymorphism in SREBP2 with serum lipid levels and obesity among children and adolescents].

OBJECTIVE: To study the relationship between rs2228314 polymorphism in sterol regulatory element binding protein 2 gene (SREBP2) and obesity, serum lipid levels in children and adolescents. METHODS: In our study, 2 030 children and adolescents aged from 7 to 18 years participated. Anthropometric measurements, including height and weight, were performed. Their serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were detected. The matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to detect rs2228314 genotypes. RESULTS: The GC/CC genotypes of rs2228314 polymorphisms had lower HDL-C levels than GG genotype [(0.10 ± 0.35) mmol/L vs. (0.14 ± 0.36) mmol/L, P=0.020]. The rs2228314 polymorphism was associated with the abnormal HDL-C level under the dominant model after adjustment for study samples, sex and age (OR=1.400, 95% CI: 1.027-1.907, P=0.033). The rs2228314 polymorphism was not associated with obesity under the dominant model after adjustment for study samples, sex, age and HDL-C level (OR=1.178,95% CI: 0.971-1.430, P=0.096). CONCLUSION: The GC/CC genotype carriers of SREBP2 rs2228314 polymorphism have higher risk of abnormal HDL-C level than the individuals with GG genotype among children and adolescents.

[Influence of diet behaviors on height among children and adolescents in China: a multiple level analysis].

OBJECTIVE: To categorize growth and development stages among children and adolescents based on height, and to explore the influences of diet behaviors on height during different growth and development stages. METHODS: Children and adolescents (7 to 18 years) with normal weights were selected using "Reference Norm for Screening Overweight and Obesity in Chinese Child and Adolescent" set up by WGOC in 2003 and "Reference Norm for Screening Underweight in Chinese Child and Adolescent" from the "2010 National Physical Fitness and Health Surveillance" data, and the variables of height and diet behaviors sorted. The growth and development stages were categorized using the hierachical cluster analysis, and the multilevel model was used to analyze influences of diet behaviors on height at different growth and development stages. RESULTS: Basis on height, there were 4 growth and development stages among the children and adolescents. In the boys, growth and development stages included Pre-GSS (growth spurt stage, GSS) including 7 to 10 years, GSS (11 to 12 years), Post-GSS (13 to 14 years), and growth stability stage (15 to 18 years); in the girls, the stages included the fast velocity GS (growth stage, GS) including 7 to 10 years, GS (11 to 12 years), Post-GS (13 to 15 years), and growth stability stage (16 to 18 years). The results of the multilevel model showed that the students' height in the urban areas were higher than in the rural areas (P<0.01), and the trend of difference between the urban and rural areas with the different growth stages was a parabola shape, the highest differences were 3.36 cm and 3.23 cm in the GSS and the fast velocity GS, respectively. There were significant influences of breakfast on height during the Pre-GSS and the fast velocity GS (P<0.01), and increased 0.40 cm and 0.57 cm, respectively. Excluding the stablility growth stage in the girls, drinking milk increased significantly height during the different growth stages (P<0.01), and the increases were gradual downtrend with the growth stages, the highest increase was 0.91 cm and 0.94 cm in Pre-GSS and the fast velocity GS, respectively. Eating eggs increased significantly height during all the growth stages (P<0.01), and the increases were the gradual uptrend with different growth stages. There were interaction effects among breakfast, drinking milk and eating eggs during the different growth stages, which was the gradual downtrend. CONCLUSION: Breakfast and drinking milk are conducive to growth during early adolescence, and the effect of eating eggs on growth is gradual uptrend with different growth stages.

[Association between early onset of menarche and anthropometry measurements among adolescent girls in China].

OBJECTIVE: To explore the association between early menarche with anthropometry measurements among adolescent girls in China. METHODS: Research material was selected from the data of 2010 Chinese National Surveys on Students Constitution and Health. Probability unit regression method was used to calculate the age of 10th percentile (P 10) at menarche and menarche age before the P 10 was defined as early menarche(9.0-11.6 years old). A total of 1072 girls with early menarche were screened. Each girl with early menarche was frequency matched with two girls who hadn't achieved menarche and with the age difference less than 0.1 yr and from the same urban or rural locations. A total of 2144 girls without menarche were screened. Participants' data of height, weight, sitting height, chest circumference, body mass index(BMI) and height and sitting height index were analyzed. t test and wilcoxon test were used to analyze the anthropometry measurements differences between the two groups, Chi square test was used to analyze the differences of overweight and obesity between the two groups. Multilevel model was used to explore the association between early menarche with anthropometry measurements and overweight and obesity. RESULTS: A total of 1072 girls with early menarche and 2144 girls without menarche. Early menarche girls' height, sitting height, chest circumference, weight and BMI were (151.42 ± 7.46) cm, (80.86 ± 4.21) cm, (73.88 ± 7.72) cm, (44.32 ± 9.35) kg, and (19.18 ± 3.03) kg/m(2), while they were (144.86 ± 7.55) cm, (76.96 ± 4.05) cm, (67.25 ± 6.94) cm, (36.07 ± 7.88) kg and (16.64 ± 2.48) kg/m(2) in girls without menarche. The difference between two groups were significant(Z values were -22.20, -23.69, -24.38, -23.12, -20.17, -6.33 respectively with all P values < 0.01). Multilevel analysis results showed that in 9.0-11.6 years old girls early menarche was associated with anthropometry measurements(all P values < 0.05). Compared with girls without menarche, girls with early menarche had a relative higher height, sitting height, weight, chest circumference, with increments of 5.28 cm, 3.37 cm, 5.53 cm, 6.37 kg, 1.79 kg/m(2). Within subgroup analysis, there were parabolic trends with age in the height, weight and sitting height differences and "U" trend in chest circumference difference between girls with early menarche and girls without menarche.In 9.0-10.8 years old, 10.9-11.0 years old and 11.1-11.2 years old groups, the risk of overweight and obesity among girls with early menarche were 2.98 (95%CI:1.92-4.63) times, 6.76 (95%CI:2.79-16.39) times, 2.99 (95%CI:1.40-6.40) times of girls without menarche. CONCLUSION: The early onset of menarche is related with height, sitting height, weight and chest circumference, and it is closely associated with overweight and obesity among adolescent girls in China.

[Effects of overweight and obesity on physical function among children and adolescents: a multilevel analysis].

OBJECTIVE: To analyze the influence of overweight and obesity on body function among children and adolescents using a multilevel model, and to provide the basis for understanding their influence. METHODS: According to the "Reference Norms for Screening Overweight and Obesity in Chinese Children and Adolescents" set up by Working Group Obesity in China (WGOC) in 2003, we screened out individuals with overweight and obesity from the data obtained from the body and health survey of Chinese children and adolescents in 2005. The samples of the non-overweight group and the overweight group were randomly selected from the screened data by 1:1 match with samples of the obesity group by gender and city/rural area, then underwent the multilevel model to explore the influence of overweight and obesity on body function. RESULTS: The single dependent variable model showed that the overweight group had significant increases in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 5.25 mmHg (1 mmHg=0.133 kPa) and 3.44 mmHg, respectively (P<0.01), when compared with the non-overweight group. There were no significant differences between the overweight and non-overweight groups in pulse and vital capacity (VC) (P>0.05), and the obesity group had significant increases in SBP, DBP, pulse and VC by 10.15 mmHg, 6.34 mmHg, 1.44 times/min and 390.04 mL, respectively (P<0.01), when compared with the non-overweight group. The multiple dependent variables model showed that the SBP, DBP and pulse of the overweight group and obesity group were significantly greater than those of non-overweight group (P<0.01). There was a significant difference between the overweight group and non-overweight group in VC (P<0.05), yet the same result was not found between the obesity group and non-overweight group (P>0.05). CONCLUSION: Overweight and obesity may cause a decline in body function among children and adolescents, and obesity has a more obvious influence on body function.

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.].

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

OBJECTIVE: Previous studies demonstrated a role of variations in sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) in obesity and blood lipids. But the associations between SCAP polymorphisms and blood pressure (BP) are not clear. This study aimed to investigate the relationship between genetic variations in SCAP and BP phenotypes in a Chinese pediatric population. METHODS: A case-control study on 702 high blood pressure (HBP) children and 1319 controls was conducted to explore the correlation between single nucleotide polymorphism markers (rs12487736 and rs12490383) of SCAP and BP phenotypes. The associations with continuous and categorical variables were examined by linear regression and logistic regression models under a dominant genetic model for the minor rs12487736 A allele and rs12490383 T allele. RESULTS: The rs12487736 polymorphism was significantly associated with systolic BP (SBP) (ß = 1.66, P = 0.003) and diastolic BP (DBP) (ß = 1.35, P = 0.024) with age, age-squared, sex, study population and body mass index (BMI) adjusted under the dominant genetic model. The rs12490383 polymorphism was significantly associated with SBP (ß = 1.71, P = 0.004) and SHBP (OR = 1.39, 95%CI: 1.04-1.86, P = 0.027). When analyzed by BMI categories, in the normal-weight children, no significant association between the SCAP polymorphisms and BP phenotypes was observed (all P > 0.05). However, in the overweight/obese children, rs12487736 was significantly associated with SBP (ß = 1.6, P = 0.019) and SHBP (OR = 1.36, 95%CI: 1.02-1.82; P = 0.037), rs12490383 was associated with SBP (ß = 2.04, P = 0.004) and SHBP (OR = 1.50, 95%CI: 1.10-2.05; P = 0.01). CONCLUSIONS: This study demonstrated that SCAP rs12487736 and rs12490383 were significantly associated with SBP and SHBP in overweight/obese Chinese children. It provided the evidence for association of SCAP with SBP.

The gene-gene interaction of INSIG-SCAP-SREBP pathway on the risk of obesity in Chinese children.

BACKGROUND: Childhood obesity has become a global public health problem in recent years. This study aimed to explore the association of genetic variants in INSIG-SCAP-SREBP pathway with obesity in Chinese children. METHODS: A case-control study was conducted, including 705 obese cases and 1,325 nonobese controls. We genotyped 15 single nucleotide polymorphisms (SNPs) of five genes in INSIG-SCAP-SREBP pathway, including insulin induced gene 1 (INSIG1), insulin induced gene 2 (INSIG2), SREBP cleavage-activating protein gene (SCAP), sterol regulatory element binding protein gene 1 (SREBP1), and sterol regulatory element binding protein gene 2 (SREBP2). We used generalized multifactor dimensionality reduction (GMDR) and logistic regression to investigate gene-gene interactions. RESULTS: Single polymorphism analyses showed that SCAP rs12487736 and rs12490383 were nominally associated with obesity. We identified a 3-locus interaction on obesity in GMDR analyses (P = 0.001), involving 3 genetic variants of INSIG2, SCAP, and SREBP2. The individuals in high-risk group of the 3-locus combinations had a 79.9% increased risk of obesity compared with those in low-risk group (OR = 1.799, 95% CI: 1.475-2.193, P = 6.61 × 10(-9)). CONCLUSION: We identified interaction of three genes in INSIG-SCAP-SREBP pathway on risk of obesity, revealing that these genes affect obesity more likely through a complex interaction pattern than single gene effect.