Yue Shen

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.

Association between Common Polymorphism near the MC4R Gene and Obesity Risk: A Systematic Review and Meta-Analysis

Background Genome-wide association studies on Europeans have shown that two polymorphisms (rs17782313, rs12970134) near the melanocortin 4 receptor (MC4R) gene were associated with increased risk of obesity. Subsequently studies among different ethnic populations have shown mixed results with some confirming and others showing inconsistent results, especially among East Asians and Africans. We performed a comprehensive meta-analysis of various studies from different ethnic populations to assess the association of the MC4R polymorphism with obesity risk. Methods We retrieved all published literature that investigated association of MC4R variants with obesity from PubMed and Embase. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Results A total of 61 studies (80,957 cases/220,223 controls) for rs17782313 polymorphism (or proxy) were included in the meta-analysis. The results suggested that rs17782313 polymorphism was significantly associated with obesity risk (ORu200a=u200a1.18, 95%CIu200a=u200a1.15–1.21, p<0.001). Similar trends were observed among subgroups of Europeans and East Asians, adults and children, studies with high quality score, and for each five MC4R polymorphisms independently. Conclusions The present meta-analysis confirms the significant association of MC4R polymorphism with risk of obesity. Further studies should be conducted to identify the causal variant and the underlying mechanisms of the identified association.

Influence of Physical Inactivity on Associations Between Single Nucleotide Polymorphisms and Genetic Predisposition to Childhood Obesity

Childhood obesity is a complex disease that is influenced by both genetic and environmental factors. The authors aim was to determine whether sedentary behavior and physical activity modulate the association between single nucleotide polymorphisms (SNPs) and obesity risk in Chinese children. A population-based study was carried out in 2,848 children (6-18 years of age) in Beijing, China, in 2004. It included 1,229 obese cases and 1,619 normal-weight controls. Lifestyle information was collected through the use of a validated questionnaire, and 6 SNPs were genotyped. The association between the 6 SNPs and obesity risk was modulated by sedentary behavior and physical activity. A higher risk of obesity was observed in children who carried the high-risk alleles of the 6 SNPs and engaged in sedentary behavior ≥2 hours/day outside of school or participated in low or moderate physical activity. Most notably, the association between 5 SNPs (Fas apoptotic inhibitory molecule 2 rs7138803, Niemann-Pick disease, type C1 rs1805081, fat mass- and obesity-associated gene rs6499640, melanocortin 4 receptor gene rs17782313, and brain-derived neurotrophic factor rs6265) and obesity risk was only observed in children who had moderate-to-low physical activity levels or engaged in sedentary behavior, regardless of which risk alleles they carried. The results indicated that encouraging less sedentary behavior and higher levels of physical activity could alleviate the influence of risk alleles on genetic predisposition to childhood obesity, thereby serving as a promising prevention strategy.

The 1425G/A SNP in PRKCH Is Associated With Ischemic Stroke and Cerebral Hemorrhage in a Chinese Population

Background and Purpose— PRKCH (the gene encoding protein kinase C &eegr;) has a role in the pathogenesis of ischemic stroke. The 1425G/A SNP in PRKCH (rs2230500) is significantly associated with ischemic stroke in Japanese. The aim of the present study is to investigate the associations in ischemic stroke and other types of stroke in the Chinese population. Methods— A total of 1209 patients with stroke and 1174 controls were examined using a case–control methodology. The 1425G/A SNP in PRKCH was genotyped by allele-specific real-time PCR assay. Results— The 1425G/A SNP in PRKCH was significantly associated with both ischemic stroke (odds ratio [OR]=1.31; 95% confidence interval [CI], 1.08 to 1.60; P=0.0058) and cerebral hemorrhage (OR=1.94; 95% CI, 1.21 to 3.10; P=0.0054) under a dominant model. Even after age- and sex-adjustment, the significant associations remained (in ischemic stroke, for AA+AG versus GG, OR=1.37, 95% CI, 1.12 to 1.67, P=0.0019; in cerebral hemorrhage, for AA+AG versus GG, OR=1.96, 95% CI, 1.21 to 3.19, P=0.0064). Conclusions— The 1425G/A SNP in PRKCH increases the risk of both ischemic stroke and cerebral hemorrhage in the Chinese population.

Study of 11 BMI-Associated Loci Identified in GWAS for Associations with Central Obesity in the Chinese Children

Objective Recent genome-wide association studies have identified many single nucleotide polymorphisms (SNPs) associated with body mass index (BMI)/generalized obesity. In this study, we aimed to examine the associations of identified SNPs with risk of central obesity in a child population from China. Methods We genotyped 11 SNPs (FTO rs9939609, MC4R rs17782313, GNPDA2 rs10938397, BDNF rs6265, FAIM2 rs7138803, NPC1 rs1805081, SEC16B rs10913469, SH2B1 rs4788102, PCSK1rs6235, KCTD15 rs29941, BAT2 rs2844479) in the Chinese children (Nu200a=u200a3502, age range 6–18 years) from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS). Based on the age- and sex- specific waist circumference (WC) standards generated in the BCAMS study, 1196 central obese cases and 2306 controls were identified. Results Of 11 studied SNPs, four SNPs and genetic risk score (GRS) based on them were statistically significantly associated with central obesity by WC criteria (FTO rs9939609: ORu200a=u200a1.29, 95%CIu200a=u200a1.10–1.50, pu200a=u200a0.001; MC4R rs17782313: ORu200a=u200a1.27, 95%CIu200a=u200a1.12–1.44, pu200a=u200a1.32×10−4; GNPDA2 rs10938397: ORu200a=u200a1.22, 95%CIu200a=u200a1.09–1.37, pu200a=u200a4.09×10−4; BDNF rs6265: ORu200a=u200a1.20, 95%CIu200a=u200a1.08–1.34, pu200a=u200a8.86×10−4; GRS: ORu200a=u200a1.25, 95%CI 1.16–1.34, pu200a=u200a2.58×10−9) after adjustment for sex, age, pubertal stage, physical activity and family history of obesity. Similar observations were made using weight-to-height ratio (WHtR) criterion. However, other SNPs were not associated with central obesity by WC as well as WHtR criterion. Conclusions Our study replicates the statistically significant association of four SNPs (FTO rs9939609, MC4R rs17782313, GNPDA2 rs10938397, BDNF rs6265) with risk of central obesity in the Chinese children.

Recapitulation of four hypertension susceptibility genes (CSK, CYP17A1, MTHFR, and FGF5) in East Asians

OBJECTIVEnA recent genome wide association study identified eight hypertension susceptibility loci in Europeans. Subsequently, several studies have investigated these associations in East Asian populations. The results of these studies, however, have been inconsistent. A meta-analysis was performed to assess the associations of the most published polymorphisms, including CSK rs1378942, CYP17A1 rs11191548, MTHFR rs17367504, and FGF5 rs16998073 polymorphisms with hypertension.nnnMETHODSnPublished literature from PubMed and Embase databases was retrieved. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed- or random-effects model.nnnRESULTSnSeven studies (16,368 cases /19,707 controls) for CSK rs1378942 polymorphism, seven studies (15,688 cases /18,784 controls) for CYP17A1 rs11191548 polymorphism, four studies (7994 cases / 12,844 controls) for MTHFR rs17367504 polymorphism, and three studies (6026 cases / 8393 controls) for FGF5 rs16998073 polymorphism were included in the meta-analysis. The results suggested that both CYP17A1 rs11191548 and FGF5 rs16998073 polymorphisms were significantly associated with hypertension risk in East Asians (CYP17A1 rs11191548 (random effect model): OR=1.16, 95% CI 1.07-1.25, p=3.59×10(-4), I(2)=78.2%, p (heterogeneity)=1.14×10(-4); FGF5 rs16998073 (random effect model): OR=1.30, 95% CI 1.23-1.37, p=6.29×10(-21), I(2)=65.0%, p (heterogeneity)=0.009); whereas no significant association was observed for CSK rs1378942 (fix effect model: OR=1.09, 95% CI 0.98-1.22, p=0.128, I(2)=0.0%, p (heterogeneity)=0.820), or MTHFR rs17367504 (fix effect model: OR=1.06, 95% CI 0.98-1.14, p=0.126, I(2)=0.0%, p (heterogeneity)=0.822).nnnCONCLUSIONnThe present meta-analysis indicated significant associations of both CYP17A1 rs11191548 and FGF5 rs16998073 polymorphisms with hypertension susceptibility in East Asians.

Physical activity modifies the associations between genetic variants and hypertension in the Chinese children.

BACKGROUNDnChildhood hypertension is a complex disease influenced by both genetic and environmental factors. We aimed to examine the effect of interactions of five polymorphisms with physical activity on blood pressure (BP)/hypertension in the Chinese children.nnnMETHODS AND RESULTSnA population-based case-control study was carried out in Beijing of China in 2004, which included 619 hypertensive cases and 2458 normal BP controls. Physical activity information was collected through the use of a validated questionnaire, and five polymorphisms were genotyped using TaqMan. In active group, there was no significant association of five polymorphisms and genetic risk score with systolic/diastolic BP (SBP/DBP) and risk of hypertension (all p > 0.05). In contrast, in inactive group, two polymorphisms and genetic risk score were significantly associated with SBP (rs17249754: β = 1.26, 95% confidence interval (CI) 0.61-1.90, p < 0.001; rs1004467: β = 0.68, 95%CI 0.03-1.32, p = 0.039; genetic risk score: β = 1.54, 95%CI 0.74-2.33, p < 0.001); three polymorphisms and genetic risk score were significantly associated with hypertension (rs17249754: odds ratio (OR) = 1.27, 95%CI 1.08-1.49, p = 0.004; rs1378942: OR = 1.25, 95%CI 1.00-1.57, p = 0.050 (marginally significant); rs16998073: OR = 1.17, 95%CI 1.01-1.37, p = 0.044; genetic risk score: OR = 1.38, 95%CI 1.13-1.68, p = 0.001).nnnCONCLUSIONSnThe present study provides evidence that interactions between recently identified variants and physical activity play important roles in the regulation of BP and development of hypertension. Physical activity should be prescribed for hypertensive children, especially for those with high risk genetic alleles.

An obesity genetic risk score is associated with metabolic syndrome in Chinese children

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with body mass index (BMI)/obesity. In this study, we aim to examine the associations of obesity related loci with risk of metabolic syndrome (MetS) in a children population from China. A total of 431 children with MetS and 3046 controls were identified based on the modified ATPIII definition. 11 SNPs (FTO rs9939609, MC4R rs17782313, GNPDA2 rs10938397, BDNF rs6265, FAIM2 rs7138803, NPC1 rs1805081, SEC16B rs10913469, SH2B1 rs4788102, PCSK1rs6235, KCTD15 rs29941, BAT2 rs2844479) were genotyped by TaqMan 7900. Of 11 SNPs, GNPDA2 rs10938397, BDNF rs6265, and FAIM2 rs7138803 were nominally associated with risk of MetS (GNPDA2 rs10938397: odds ratio (OR)=1.21, 95% confidence interval (CI)=1.04-1.40, P=0.016; BDNF rs6265: OR=1.19, 95% CI=1.03-1.39, P=0.021; FAIM2 rs7138803: OR=1.20, 95% CI=1.02-1.40, P=0.025); genetic risk score (GRS) was significantly associated with risk of MetS (OR=1.09, 95% CI=1.04-1.15, P=5.26×10(-4)). After further adjustment for BMI, none of SNPs were associated with risk of MetS (all P>0.05); the association between GRS and risk of MetS remained nominally (OR=1.02, 95%CI=0.96-1.08, P=0.557). However, after correction for multiple testing, only GRS was statistically associated with risk of MetS in the model without adjustment for BMI. The present study demonstrated that there were nominal associations of GNPDA2 rs10938397, BDNF rs6265, and FAIM2 rs7138803 with risk of MetS. The SNPs in combination have a significant effect on risk of MetS among Chinese children. These associations above were mediated by adiposity.

STK39 Polymorphism Is Associated with Essential Hypertension: A Systematic Review and Meta-Analysis

Background A recent genome-wide association study identified STK39as a candidate gene for blood pressure (BP) in Europeans. Subsequently, several studies have attempted to replicate the association across different ethnic populations. However, the results have been inconsistent. Objective and Methods We performed a meta-analysis to elucidate the association between the STK39 rs3754777 polymorphism (or proxy) and hypertension. Published literature from PubMed and Embase databases were retrieved and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Results Using appropriate inclusion/exclusion criteria, we identified 10 studies that included 21, 863 hypertensive cases and 24, 480 controls from different ethnicities. The meta-analysis showed a significant association of STK39 rs3754777 variant with hypertension (ORu200a=u200a1.10, 95%CIu200a=u200a1.06–1.15, pu200a=u200a7.95×10−6). Further subgroup analysis by ethnicity suggested that the association was significant in Europeans (ORu200a=u200a1.08, 95% CIu200a=u200a1.03–1.14, pu200a=u200a0.002) and in East Asians (ORu200a=u200a1.16, 95%CIu200a=u200a1.07–1.25, pu200a=u200a4.34×10−4), but not in Africans (ORu200a=u200a1.01, 95%CI 0.80–1.27, pu200a=u200a0.932). We further confirmed the positive association by sensitivity analysis. No publication bias was detected (Begg’s test, pu200a=u200a0.721; Egger’s test, pu200a=u200a0.744). Conclusions The present meta-analysis confirms the significant association of STK39 polymorphism with susceptibility to hypertension in Europeans and East Asians. Future studies should include gene–gene and gene–environment interactions to investigate the identified association.