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.

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 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.

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.

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)

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.

The association between fetal-stage exposure to the China famine and risk of diabetes mellitus in adulthood: results from the China health and retirement longitudinal study.

BACKGROUND: The associations of famine exposure with diabetes risk in adulthood are still unclear. This study aimed to explore the association between famine exposure in early life and risk of diabetes in adulthood. METHODS: A total of 4138 subjects were selected from the data of the China Health and Retirement Longitudinal Study (CHARLS) 2011-2012. Diabetes was diagnosed as fasting plasma glucose (FPG) ≥7.0 mmol/L, glycated haemoglobin (HbA1C) > 6.5%, or self-reported diabetes. Birthdates of subjects were used to categorize famine exposure groups. The association of fetal-stage famine exposure with diabetes risk in adults was assessed using logistics regression model. RESULTS: The prevalence of diabetes in the non-exposed, fetal-stage exposed, infant-stage exposed, and preschool-stage exposed groups were 9.0, 13.6, 12.7 and 10.8%, respectively. Compared with the age-balanced control group, the fetal-stage exposed group was associated with the elevated risk of diabetes in later life after adjusting for covariates (OR = 1.37; 95%CI: 1.09-1.72; P = 0.008). Stratified analysis showed that the association between prenatal famine exposure and diabetes risk in adulthood was comparable between severely affected areas and less severely affected areas (P for interaction =0.153). CONCLUSIONS: Famine exposure in fetal stages was associated with the elevated diabetes risk in adults, which could be the critical periods for relative intervention.

Interaction between obesity and the Hypoxia Inducible Factor 3 Alpha Subunit rs3826795 polymorphism in relation with plasma alanine aminotransferase.

BACKGROUND: Hypoxia Inducible Factor 3 Alpha Subunit (HIF3A) DNA has been demonstrated to be associated with obesity in the methylation level, and it also has a Body Mass Index (BMI)-independent association with plasma alanine aminotransferase (ALT). However, the relation among obesity, plasma ALT, HIF3A polymorphism and methylation remains unclear. This study aims to identify the association between HIF3A polymorphism and plasma ALT, and further to determine whether the effect of HIF3A polymorphism on ALT could be modified by obesity or mediated by DNA methylation. METHODS: The HIF3A rs3826795 polymorphism was genotyped in a case-control study including 2030 Chinese children aged 7-18 years (705 obese cases and 1325 non-obese controls). Furthermore, the HIF3A DNA methylation of the peripheral blood was measured in 110 severely obese children and 110 age- and gender- matched normal-weight controls. RESULTS: There was no overall association between the HIF3A rs3826795 polymorphism and ALT. A significant interaction between obesity and rs3826795 in relation with ALT was found (P inter = 0.042), with rs3826795 G-allele number elevating ALT significantly only in obese children (ß' = 0.075, P = 0.037), but not in non-obese children (ß' = -0.009, P = 0.741). Additionally, a mediation effect of HIF3A methylation was found in the association between the HIF3A rs3826795 polymorphism and ALT among obese children (ß' = 0.242, P = 0.014). CONCLUSION: This is the first study to report the interaction between obesity and HIF3A gene in relation with ALT, and also to reveal a mediation effect among the HIF3A polymorphism, methylation and ALT. This study provides new evidence to the function of HIF3A gene, which would be helpful for future risk assessment and personalized treatment of liver diseases.

Physical activity and sedentary behavior can modulate the effect of the PNPLA3 variant on childhood NAFLD: a case-control study in a Chinese population.

BACKGROUND: The patatin like phospholipase containing domain 3 gene (PNPLA3) rs738409 C > G polymorphism, one of the most important gene polymorphisms involved in hepatic steatosis, has been reported to interact with different nutrients and dietary patterns on Non-Alcoholic Fatty Liver Disease (NAFLD), but no studies have focused on its interaction with physical activity or sedentary behavior. Therefore, this study aims at determining whether physical activity or sedentary behavior could modulate the effect of the PNPLA3 variant on childhood NAFLD. METHODS: A case-control study was conducted including 1027 Chinese children aged 7-18 years old (162 children with NAFLD and 865 children without). The anthropometric measurements, liver ultrasound examination, questionnaires and genotyping of the PNPLA3 rs738409 polymorphism were performed. RESULTS: Stratified analyses showed that the proportions of NAFLD increased with the G-allele number only in children who did not have enough physical activity (physical activity < 1 h/d) (OR 3.05, 95% CI 1.82-5.12, P < 0.001), and in children with a sedentary lifestyle (sedentary behavior ≥ 2 h/d) (OR 3.41, 95% CI 1.88-6.18, P < 0.001). Significant interactions on childhood NAFLD were found between the G-allele number in the PNPLA3 rs738409 polymorphism and behaviors, including physical activity (P = 0.001), sedentary behavior (P = 0.010) and the combination of physical activity and sedentary behavior (P < 0.001). CONCLUSION: This is the first study to report the interaction between the PNPLA3 rs738409 polymorphism and physical activity or sedentary behavior on NAFLD, providing new clues on the function of the PNPLA3 gene, which will also be useful for future risk assessment and personalized treatment of NAFLD.

Association of common variants identified by recent genome-wide association studies with obesity in Chinese children: a case-control study.

BACKGROUND: Large-scale genome-wide association studies have identified multiple genetic variants that are associated with elevated body mass index (BMI) or the risk of obesity in Caucasian or Asian populations. We examined whether these variants are individually associated with obesity in Chinese children, and also assessed their cumulative effects and predictive value for obesity risk in Chinese children. METHODS: We genotyped 40 single nucleotide polymorphisms (SNPs) and conducted association analyses for 32/40 SNPs with an estimated minor allele frequency >1% in 2 030 unrelated Chinese children, including 607 normal-weight, 718 overweight, and 705 obese individuals from two cross-sectional study groups. Logistic regression and linear regression under the additive model were used to examine associations, and the area under the receiver operating characteristic curve (AUCROC) was reported as prediction summary. RESULTS: We identified obesity association for 6 SNPs near SEC16B, RBJ, CDKAL1, TFAP2B, MAP2K5 and FTO (odds ratios (ORs) ranged from 1.19 to 1.41, nominal two-sided P-values < 0.05). Association (Bonferroni corrected) of rs543874 near SEC16B and rs2241423 near MAP2K5 had presumably stronger effects on obesity in Chinese children than in Caucasian populations. Their risk alleles were also associated with BMI standard deviation score (BMI-SDS) variability. We demonstrated the cumulative effects of the 32 SNPs on obesity risk (per risk allele: OR = 1.06, 95 % CI: 1.03-1.11, P = 4.84 × 10(-4)) and BMI-SDS (ß = 0.04, 95% CI: 0.02-0.06, P = 3.69 × 10(-7)). The difference in AUCROC for a model with covariates (age, age square, sex and study group) and the model including covariates and all 32 SNPs was 2.8% (P = 0.0002). CONCLUSION: While six SNPs were individually associated with obesity in Chinese children, the 32 common variants identified by recent GWA studies had cumulative effects and resulted in a limited increase in the AUCROC predictive value for childhood obesity.

Does local ambient temperature impact children's blood pressure? A Chinese National Survey.

BACKGROUND: Several studies demonstrated a short-term association between ambient temperature and blood pressure. However, few studies have assessed the long-term effect of ambient temperature on children's blood pressure. The present study aimed to investigate the association between long-term exposure to local ambient temperature and children's blood pressure in China. METHODS: We analyzed the systolic (SBP) and diastolic blood pressure (DBP) data of 71,763 children from 2010 Chinese National Survey on Students' Construction and Health (CHNSCH), and local annual average ambient temperature, relative humidity, air pollutants data from China Meteorological Administration and Ministry of Environment Protection of China. We used generalized additive model (GAM) with non-linear function to examine the effects of ambient temperature on children's blood pressure. RESULTS: The results showed that decrease of ambient temperature was negatively associated with increase of both SBP and DBP in Chinese children while adjusting for individual characteristics, socioeconomic conditions, air pollutants and relative humidity. The largest alteration of SBP related to the temperature difference was observed from 20.4 to 9.6 °C, with 9.0 mmHg (95 % CI: 8.4, 9.5) increase in SBP, while the largest alteration of DBP was observed from 21.7 to 10.2 °C, with 6.1 mmHg (95 % CI: 5.6, 6.6) increase in DBP. However, when temperature below 9.6 and 10.2 °C, SBP and DBP started to decrease, which might be caused by the use of heating system in the extreme cold areas. CONCLUSIONS: Public health policy should be improved for protecting children's cardiovascular health from adverse effects of low temperature. Development of heating system in moderate cold area might be a good solution.

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.

[Mutation screening and function prediction of melanocortin-4 receptor gene in obese children].

OBJECTIVE: To screen the coding region of melanocortin-4 receptor gene (MC4R) for mutations in children, analyze the association of the identified variants with obesity-related phenotypes, and predict the potential functions of the identified variants. METHODS: A case-control study was conducted in 160 severely obese children and 100 normal-weight controls, all aged 7-18 years. Their anthropometric data were collected and blood tests were performed. The coding region of MC4R gene was screened by polymerase chain reaction (PCR), single strand conformation polymorphism and sequencing, and the potential functions of the identified variants were predicted by related online databases. RESULTS: Three heterozygous missense mutations were identified in obese children (Val95Ile, Val166Ile and Val179Ala), and one heterozygous missense mutation was found in controls (Met218Thr). Val103Ile variant was found to be carried by seven subjects in the obese group and six in the control group (P>0.05). Val179Ala was a newly identified heterozygous mutation. No significant differences in BMI, weight, waist circumstance, hip circumstance, serum lipid parameters, fasting glucose, and body fat percentage were found between Val95Ile, Val166Ile or Val179Ala mutation carriers and non-carriers in obese children. The function prediction of the variants showed that all the five identified variants influenced the protein function. CONCLUSIONS: Five variants were identified in the coding region of MC4R gene, among which Val179Ala was newly identified. All the five variants might influence the protein function as evidenced by online prediction.

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.

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.

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.