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.

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.

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.

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.].

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)

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.

Waist-hip ratio related genetic loci are associated with risk of impaired fasting glucose in Chinese children: a case control study.

BACKGROUND: The meta-analyses of genome-wide association studies identified several waist-hip ratio (WHR) related loci in individuals of European ancestry. Since the pattern of fat distribution and the relationship between fat distribution and glucose metabolism disturbance in Chinese are different from those in Europeans, the present study aimed to explore the individual and cumulative effects of WHR-related loci on glycemic phenotypes in Chinese children. METHODS: A total of 2030 children were recruited from two independent studies. Eleven single nucleotide polymorphisms (SNPs) were selected and genotyped using matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). Logistic regression and linear regression model were used to examine the association of 11 SNPs and genetic risk score (GRS) with impaired fasting glucose (IFG) and fasting plasma glucose (FPG), respectively. RESULTS: Three SNPs (rs6795735, rs984222 and rs1011731) were nominally associated with IFG (all P < 0.05). Each WHR-increasing (C) allele of rs6795735 (ADAMTS9) was associated with a 40.1% increased risk of IFG (OR = 1.401, 95% CI = 1.131-1.735, P = 0.002), which remained significant after Bonferroni correction. We observed no association of both weighted and unweighted GRS with FPG and IFG (all P > 0.05). CONCLUSIONS: We identified individual effects of rs6795735 (ADAMTS9), rs984222 (TBX15-WARS2), and rs1011731 (DNM3-PIGC) on glycemic phenotypes in Chinese children for the first time. The study suggests that genetic predisposition to central obesity is associated with impaired fasting glucose, providing more evidence for the pathogenesis of diabetes.

Geographic variation in Chinese children' forced vital capacity and its association with long-term exposure to local PM10: a national cross-sectional study.

The purpose of this study was to estimate the association between Chinese children's forced vital capacity (FVC) and particulate matter with aerodynamic diameter ≤10 µm (PM10). The FVC data of 71,763 children aged 7 to 18 was collected from 2010 Chinese National Survey on Students' Construction and Health (CNSSCH). The local annual average concentration of PM10, relative humidity, ambient temperature, and other air pollutant data of 30 cities was collected from China Meteorological Administration and Ministry of Environment Protection of China. Then, we used generalized additive model (GAM) to estimate the association between children's FVC and PM10. The obvious geographic variation in FVC was found in children of 30 Chinese cities ranging from 1647 ml in Xining to 2571 ml in Beijing. The annual average concentration of PM10 was also different, ranging from 40 µg/m3 in Haikou to 155 µg/m3 in Lanzhou. After adjusted individual characteristics, socioeconomic conditions, ambient temperature, relative humidity, and other air pollutants (e.g., NO2 and SO2) in the generalized additive model, we found that the increase of PM10 was associated with decrease of FVC in Chinese children. A 10-µg/m3 increase of PM10 was associated with 1.33-ml decrease in FVC (95% confidence interval: -2.18 to -0.47). We also found a larger effect estimate of PM10 on FVC in boys than that in girls. Consistent associations were found in both physically inactive and active children. The increase of PM10 was associated with decrease of children's FVC. We should develop proper public health policy to protect children's respiratory health during growth and development in polluted areas.

Association Study of Three Gene Polymorphisms Recently Identified by a Genome-Wide Association Study with Obesity-Related Phenotypes in Chinese Children.

OBJECTIVE: This study aimed to examine associations of three single-nucleotide polymorphisms (SNPs) with obesity-related phenotypes in Chinese children. These SNPs were identified by a recent genome-wide association (GWA) study among European children. Given that varied genetic backgrounds across different ethnicity may result in different association, it is necessary to study these associations in a different ethnic population. METHODS: A total of 3,922 children, including 2,191 normal-weight, 873 overweight and 858 obese children, from three independent studies were included in the study. Logistic and linear regressions were performed, and meta-analyses were conducted to assess the associations between the SNPs and obesity-related phenotypes. RESULTS: The pooled odds ratios of the A-allele of rs564343 in PACS1 for obesity and severe obesity were 1.180 (p = 0.03) and 1.312 (p = 0.004), respectively. We also found that rs564343 was nominally associated with BMI, BMI standard deviation score (BMI-SDS), waist circumference, and waist-to-height ratio (p < 0.05). CONCLUSIONS: We showed for the first time that the rs564343 in PACS1 was associated with risk of severe obesity in a non-European population. This SNP was also found to be associated with common obesity and various obesity-related phenotypes in Chinese children, which had not been reported in the original study. The results demonstrated the value of conducting genetic researches in populations with different ethnicity.

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.

Physical Activity and Sedentary Behaviors Modify the Association between Melanocortin 4 Receptor Gene Variant and Obesity in Chinese Children and Adolescents.

Effects of MC4R variants in previous Chinese population studies were inconsistent. Gene-environment interactions might influence the effect of MC4R variants on obesity, which was still unclear. We performed the study to clarify the association of variants near MC4R gene with obesity-related phenotypes and gene-environment interactions in Chinese children and adolescents. Two common variants (rs12970134 and rs17782313) near MC4R were genotyped in 2179 children and adolescents aged 7-18 years in Beijing of China. Associations between the variants and obesity-related phenotypes together with gene-environment interactions were analyzed. The A-alleles of rs12970134 were nominally associated with risk of overweight/obesity (Odds Ratios (OR) = 1.21, 95%CI: 1.03-1.44, P = 0.025) and BMI (ß = 0.33 kg/m2, 95%CI: 0.02-0.63, P = 0.025), respectively. The rs12970134 was also associated with HDL-C (ß = -0.03mmol/L per A-allele, 95%CI: -0.05, -0.01, P = 0.013) independent of BMI. In the further analysis, we found the significant interaction of rs12970134 and physical activity/sedentary behaviors on BMI (Pinteraction = 0.043). The rs12970134 was found to be associated with BMI only in children with physical activity<1h/d and sedentary behaviors ≥2h/d (BMI: ß = 1.27 kg/m2, 95%CI: 0.10-2.45, P = 0.034). The association was not detected in their counterparts with physical activity≥1h/d or sedentary behaviors <2h/d. We identified the effect of MC4R rs12970134 on overweight/obesity and BMI, and we also found physical activity and sedentary behaviors modified the association between the rs12970134 and BMI in Chinese children and adolescents.

Association between children's forced vital capacity and long-term exposure to local ambient temperature in China: A national cross-sectional survey.

It is well documented that short-term exposure to extreme ambient temperature is associated with respiratory disorder. However, few studies have assessed the long-term effect of temperature on children's lung function. The present study aimed to investigate the association between long-term exposure to local ambient temperature and children's forced vital capacity (FVC) in China. We analyzed the FVC data of 71,768 children from the 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. Generalized additive model (GAM) with non-linear function was used to examine the effect of ambient temperature on children's FVC. The results showed that low temperature was significantly associated with decrease of FVC in Chinese children within certain temperature range while adjusting for individual characteristics, socioeconomic conditions, air pollutants and relative humidity. The largest alteration of FVC related to the annual average temperature difference among cities from 20.4°C to 4.5°C was observed, being 242.7ml (95%CI: 220.0, 265.3) decrease in FVC. The similar association was found in both physically active and inactive children, while the largest alteration of FVC related to the temperature difference reached 329.1ml (95%CI: 296.7, 361.6) in physically active children and 290.5ml (95%CI: 255.7, 325.3) in physically inactive ones. Public health policy should be developed for protecting children's respiratory health during growth and development in some areas with cold weather. Key message What is the key question? Few studies have assessed the long-term effect of temperature on children's forced vital capacity (FVC). We analyzed the Chinese national survey data to clarify the association between children's forced vital capacity and long-term exposure to local ambient temperature. What is the bottom line? Our study found that low temperature was significantly associated with decrease of forced vital capacity in children of 30 cities in China. The largest alteration of FVC related to the temperature difference from 20.4°C to 4.5°C was observed, being 242.7ml (95%CI: 220.0, 265.3) decrease in FVC. Why read on? The presented study provide some evidence about long-term effect of temperature on children's respiratory health and public health policy should be developed for protecting children from adverse effects of low temperature on their respiratory health during growth and development in some areas with cold weather.

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.

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.

Gender-Specific Effect of -102G>A Polymorphism in Insulin Induced Gene 2 on Obesity in Chinese Children.

Background. Insulin induced gene 2 (INSIG2) encodes a protein that has a biological effect on regulation of adipocyte metabolism and body weight. This study aimed to investigate the association of INSIG2 gene -102G>A polymorphism with obesity related phenotypes in Chinese children and test gender-specific effects. Methods. The 2,030 independent individuals aged from 7 to 18 years, including 705 obese cases and 1,325 nonobese controls, were recruited from local schools. We measured the obesity-related phenotypes and detected the serum lipids. We genotype -102G>A polymorphism by using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results. In all individuals, we found that the GG/GA genotype of INSIG2 -102G>A polymorphism was associated with risk of severe obesity (OR = 1.62, 95% CI: 1.11-2.36, and P = 0.012) under the dominant model. The association with severe obesity existed only in boys (OR = 1.91, 95% CI: 1.15-3.17, P = 0.012). The GG/GA genotype of -102G>A polymorphism was also associated with higher waist circumference (ß = 2.61 cm, P = 0.031) in boys. No similar association was found in girls. The polymorphism was not associated with other obesity-related phenotypes, neither in all individuals nor in gender-specific population. Conclusions. This study identified a gender-specific effect of INSIG2 -102G>A polymorphism on risk of severe obesity and waist circumference in Chinese boys.

The rs2237892 Polymorphism in KCNQ1 Influences Gestational Diabetes Mellitus and Glucose Levels: A Case-Control Study and Meta-Analysis.

OBJECTIVE: Recent genetic studies have shown that potassium voltage-gated channel, KQT-like subfamily, member1 (KCNQ1) gene is related to gestational diabetes mellitus (GDM). However, studies for the rs2237892 polymorphism in KCNQ1 and GDM remain conflicting in Asians. Furthermore, associations of this polymorphism with glucose levels during oral glucose tolerance test (OGTT) have not been described in Chinese pregnant women. The present study aimed to provide evidence for the associations of rs2237892 in KCNQ1 with GDM and glucose levels, and to systematically evaluate the effect of rs2237892 on GDM in Asians. METHODS: A case-control study on 562 women with GDM and 453 controls was conducted in Beijing, China. The association of rs2237892 with risk of GDM was analyzed using logistic regression. The associations with quantitative glucose levels were assessed using linear regression models. A meta-analysis including the present case-control study and four previously published reports in Asians was conducted. RESULTS: The rs2237892 polymorphism in KCNQ1 was associated with GDM (OR (95%CI) =1.99(1.26-3.15)). Additionally, the polymorphism was associated with levels of 1h and 2h glucose during OGTT. The pre-pregnancy BMI, age and genotypes of KCNQ1 polymorphism were independent risk factors of GDM. Subsequently, we performed a meta-analysis in Asians. In total, C-allele carriers of rs2237892 polymorphism had a 50% higher risk for GDM (OR (95%CI) =1.50(1.15-1.78)). CONCLUSION: The study demonstrated for the first time that the KCNQ1 rs2237892 polymorphism was associated with GDM and glucose levels in Chinese women. The study provides systematic evidence for the association between this polymorphism and GDM in Asians.

Fine Mapping of a GWAS-Derived Obesity Candidate Region on Chromosome 16p11.2.

INTRODUCTION: Large-scale genome-wide association studies (GWASs) have identified 97 chromosomal loci associated with increased body mass index in population-based studies on adults. One of these SNPs, rs7359397, tags a large region (approx. 1MB) with high linkage disequilibrium (r2>0.7), which comprises five genes (SH2B1, APOBR, sulfotransferases: SULT1A1 and SULT1A2, TUFM). We had previously described a rare mutation in SH2B1 solely identified in extremely obese individuals but not in lean controls. METHODS: The coding regions of the genes APOBR, SULT1A1, SULT1A2, and TUFM were screened for mutations (dHPLC, SSCP, Sanger re-sequencing) in 95 extremely obese children and adolescents. Detected non-synonymous variants were genotyped (TaqMan SNP Genotyping, MALDI TOF, PCR-RFLP) in independent large study groups (up to 3,210 extremely obese/overweight cases, 485 lean controls and 615 obesity trios). In silico tools were used for the prediction of potential functional effects of detected variants. RESULTS: Except for TUFM we detected non-synonymous variants in all screened genes. Two polymorphisms rs180743 (APOBR p.Pro428Ala) and rs3833080 (APOBR p.Gly369_Asp370del9) showed nominal association to (extreme) obesity (uncorrected p = 0.003 and p = 0.002, respectively). In silico analyses predicted a functional implication for rs180743 (APOBR p.Pro428Ala). Both APOBR variants are located in the repetitive region with unknown function. CONCLUSION: Variants in APOBR contributed as strongly as variants in SH2B1 to the association with extreme obesity in the chromosomal region chr16p11.2. In silico analyses implied no functional effect of several of the detected variants. Further in vitro or in vivo analyses on the functional implications of the obesity associated variants are warranted.

[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.