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The association of obesity susceptibility variants with change in body mass index (BMI) across the life course is not well understood. In ancestry-stratified models of 5962 European American (EA), 2080 African American (AA) and 1582 Hispanic American (HA) individuals from the National Longitudinal Study of Adolescent to Adult Health (Add Health), we examined associations between 34 obesity single-nucleotide polymorphisms (SNPs) with per year change in BMI, measured by the slope from a growth-curve analysis of two or more BMI measurements between adolescence and young adulthood. For SNPs nominally associated with BMI change (P<0.05), we interrogated age differences within data collection Wave and time differences between age categories that overlapped between Waves. We found SNPs in/near FTO, MC4R, MTCH2, TFAP2B, SEC16B and TMEM18 were significantly associated (P<0.0015≈0.05/34) with BMI change in EA and the ancestry-combined meta-analysis. rs9939609 in FTO met genome-wide significance at P<5e-08 in the EA and ancestry-combined analysis, respectively [Beta(se)=0.025(0.004);Beta(se)=0.021(0.003)]. No SNPs were significant after Bonferroni correction in AA or HA, although five SNPs in AA and four SNPs in HA were nominally significant (P<0.05). In EA and the ancestry-combined meta-analysis, rs3817334 near MTCH2 showed larger effects in younger respondents, whereas rs987237 near TFAP2B, showed larger effects in older respondents across all Waves. Differences in effect estimates across time for MTCH2 and TFAP2B are suggestive of either era or cohort effects. The observed association between variants in/near FTO, MC4R, MTCH2, TFAP2B, SEC16B and TMEM18 with change in BMI from adolescence to young adulthood suggest that the genetic effect of BMI loci varies over time in a complex manner, highlighting the importance of investigating loci influencing obesity risk across the life course. Show less

The prevalence of childhood obesity has been dramatically increasing in developing countries as it has been reported for developed nations. Identifying susceptibility genes in early life could provide the foundations for interventions in lifestyle to prevent obese children to become obese adults. The objective of this study was to evaluate the influence of genetic variants related to obesity identified by genome-wide association studies (MC4R, TMEM18, KCTD15, SH2B1, SEC16B, BDNF, NEGR1, OLFM4 and HOXB5 genes) on anthropometric and dietary phenotypes in two Brazilian cohorts followed-up since birth. There were 745 children examined at birth, after 1 year and after 3.5 years of follow-up. Ten single nucleotide polymorphisms were genotyped. Anthropometric and dietary parameters were compared among genotypes. Children were classified as overweight when body mass index Z-score was >+1. Overweight prevalence was 30.7% at 3.5 years old. Significant associations were identified at 3.5 years old for TMEM18 rs6548238, NEGR1 rs2815752, BDNF rs10767664 and rs6265 (1 year old and 3.5 years old) with anthropometric phenotypes and at 3.5 years old for SEC16B rs10913469 with dietary parameters. Our results indicate that genetic variants in/near these genes contribute to obesity susceptibility in childhood and highlight the age at which they begin to affect obesity-related phenotypes. Show less

Specific targets for most obesity candidate genes discovered by genomewide association studies remain unknown. Such genes are often highly expressed in the hypothalamus, indicating their role in energy homeostasis. We aimed to evaluate the associations of selected gene variants with adiposity and dietary traits. Anthropometric parameters, fat mass, dietary intake (total energy, fat, protein, carbohydrate, fiber, and calcium) and 10 gene variants (in/near TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R and FTO) were analyzed in 1953 Czech individuals aged 10.0 to 18.0 years (1035 nonoverweight and 918 overweight: body mass index [BMI] ≥90th percentile). Obesity risk alleles of TMEM18 rs7561317, SEC16B rs10913469, and FTO rs9939609 were related to increased body weight and BMI (P < .005). The FTO variant also showed a significant positive association with waist circumference and fat mass (P < .001). Overweight adolescents had a lower total energy intake (P < .001) but a higher percentage of fat (P = .009) and protein intake (P < .001) than the nonoverweight subjects. There was also a lower calcium intake in the overweight group (P < .001). An association with at least one component of dietary intake was found in 3 of 10 studied gene variants. The MC4R rs17782313 was associated negatively with protein (P = .012) and positively associated with fiber (P = .032) intakes. The obesity risk alleles of BDNF rs925946 and FTO rs9939609 were related to a lower calcium intake (P = .001 and .037). The effects of FTO and MC4R variants, however, disappeared after corrections for multiple testing. Our results suggest that the common BDNF variant may influence dietary calcium intake independent of BMI. Show less

Both, common gene variants and human adenovirus 36 (Adv36) are involved in the pathogenesis of obesity. The potential relationship between these two pathogenic factors has not yet been investigated. The aim of our study was to examine the association of obesity susceptibility loci with Adv36 status. Genotyping of ten gene variants (in/near TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R, FTO) and analysis of Adv36 antibodies was performed in 1,027 Czech adolescents aged 13.0-17.9 years. Variants of two genes (PCSK1 and BDNF) were associated with Adv36 seropositivity. A higher prevalence of Adv36 antibody positivity was observed in obesity risk allele carriers of PCSK1 rs6232, rs6235 and BDNF rs4923461 vs. non-carriers (chi(2)=6.59, p=0.010; chi(2)=7.56, p=0.023 and chi(2)=6.84, p=0.033, respectively). The increased risk of Adv36 positivity was also found in PCSK1 variants: rs6232 (OR=1.67, 95 % CI 1.11-2.49, p=0.016) and rs6235 (OR=1.34, 95 % CI 1.08-1.67, p=0.010). PCSK1 rs6232 and BDNF rs925946 variants were closely associated with Adv36 status in boys and girls, respectively (chi(2)=5.09, p=0.024; chi(2)=7.29, p=0.026). Furthermore, PCSK1 rs6235 risk allele was related to Adv36 seropositivity (chi(2)=6.85, p=0.033) in overweight/obese subgroup. In conclusion, our results suggest that obesity risk variants of PCSK1 and BDNF genes may be related to Adv36 infection. Show less

Recent findings have reemphasized the importance of epistasis, or gene-gene interactions, as a contributing factor to the unexplained heritability of obesity. Network-based methods such as statistical epistasis networks (SEN), present an intuitive framework to address the computational challenge of studying pairwise interactions between thousands of genetic variants. In this study, we aimed to analyze pairwise interactions that are associated with Body Mass Index (BMI) between SNPs from twelve genes robustly associated with obesity (BDNF, ETV5, FAIM2, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18). We used information gain measures to identify all SNP-SNP interactions among and between these genes that were related to obesity (BMI > 30 kg/m(2)) within the Framingham Heart Study Cohort; interactions exceeding a certain threshold were used to build an SEN. We also quantified whether interactions tend to occur more between SNPs from the same gene (dyadicity) or between SNPs from different genes (heterophilicity). We identified a highly connected SEN of 709 SNPs and 1241 SNP-SNP interactions. Combining the SEN framework with dyadicity and heterophilicity analyses, we found 1 dyadic gene (TMEM18, P-value = 0.047) and 3 heterophilic genes (KCTD15, P-value = 0.045; SH2B1, P-value = 0.003; and TMEM18, P-value = 0.001). We also identified a lncRNA SNP (rs4358154) as a key node within the SEN using multiple network measures. This study presents an analytical framework to characterize the global landscape of genetic interactions from genome-wide arrays and also to discover nodes of potential biological significance within the identified network. Show less

Obesity is a well-known risk factor for type 2 diabetes. Genome-wide association studies have identified a number of genetic loci associated with obesity. The aim of this study is to examine the contribution of obesity-related genomic loci to type 2 diabetes in a Chinese population. We successfully genotyped 18 obesity-related single nucleotide polymorphisms among 5338 type 2 diabetic patients and 4663 controls. Both individual and joint effects of these single nucleotide polymorphisms on type 2 diabetes and quantitative glycemic traits (assessing β-cell function and insulin resistance) were analyzed using logistic and linear regression models, respectively. Two single nucleotide polymorphisms near MC4R and GNPDA2 genes were significantly associated with type 2 diabetes before adjusting for body mass index and waist circumference (OR (95% CI) = 1.14 (1.06, 1.22) for the A allele of rs12970134, P = 4.75×10(-4); OR (95% CI) = 1.10 (1.03, 1.17) for the G allele of rs10938397, P = 4.54×10(-3)). When body mass index and waist circumference were further adjusted, the association of MC4R with type 2 diabetes remained significant (P = 1.81×10(-2)) and that of GNPDA2 was attenuated (P = 1.26×10(-1)), suggesting the effect of the locus including GNPDA2 on type 2 diabetes may be mediated through obesity. Single nucleotide polymorphism rs2260000 within BAT2 was significantly associated with type 2 diabetes after adjusting for body mass index and waist circumference (P = 1.04×10(-2)). In addition, four single nucleotide polymorphisms (near or within SEC16B, BDNF, MAF and PRL genes) showed significant associations with quantitative glycemic traits in controls even after adjusting for body mass index and waist circumference (all P values<0.05). This study indicates that obesity-related genomic loci were associated with type 2 diabetes and glycemic traits in the Han Chinese population. Show less

To examine the impact of single nucleotide polymorphisms in obesity-related genes on risk of obesity and metabolic disorder in childhood. A total of 3 503 Chinese children aged 6 to 18 years 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). Body size parameters were assessed and venipuncture blood samples were collected after a 12-hour overnight fast. Plasma glucose, insulin and serum lipid profiles were measured.Genomic DNA was isolated from peripheral blood white cells using the salt fractionation method. A total of 11 single nucleotide polymorphisms were genotyped by TaqMan allelic discrimination assays with the GeneAmp 7900 sequence detection system (Applied Biosystems, Foster City, CA, USA) (FTO rs9939609, MC4R rs17782313, GNPDA2 rs10938397, FAIM2 rs7138803, BDNF rs6265, NPC1 rs1805081, PCSK1 rs6235, KCTD15 rs29941, BAT2 rs2844479, SEC16B rs10913469 and SH2B1 rs4788102). Multiple factor analysis was performed to estimate the association between the variant and obesity-related traits. The false discovery rate (FDR) approach was used to correct for multiple comparisons. After sex, age and pubertal stage adjustment and correction for multiple testing, the rs9939609-A, rs17782313-C, rs10938397-G, and rs7138803-A alleles were associated with higher BMI (β = 0.352-0.747), fat mass percentage(β = 0.568-1.113), waist circumference (β = 0.885-1.649) and waist-to-height ratio(β = 0.005-0.010) (all P values < 0.01) in Chinese children. The rs6265-G allele increased BMI(β = 0.251, P = 0.020). The rs9939609-A, rs17782313-C, and rs10938397-G and rs6265-G alleles were also associated with risk of obesity (OR = 1.386, 95%CI:1.171-1.642; OR = 1.367, 95%CI:1.196-1.563; OR = 1.242, 95%CI:1.102-1.400; OR = 1.156, 95%CI:1.031-1.296).Rs7138803 was associated with risk of obesity only in boys (OR = 1.234, 95%CI:1.043-1.460). GNPDA2 rs10938397-G allele was associated with risk of insulin resistance(OR = 1.205, 95%CI:1.069-1.359), but there was no significance after adjusting for BMI. The association of FTO rs9939609-A, MC4R rs17782313-C, GNPDA2 rs10938397-G, and FAIM2 rs7138803-A with higher BMI, fat mass percentage, waist circumference, and waist-to height ratio and risk of obesity, and BDNF rs6265-G allele may increase BMI and obesity risk in Chinese children. GNPDA2 rs10938397-G may increase the risk of childhood insulin resistance depending on BMI. Show less

Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration. Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles. None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed. In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI. Show less

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. Show less

The objective of this study was the description of a valid genetic risk score (GRS) to predict individuals with high susceptibility to childhood overweight by their genetic profiles. Case-control study including a group of children with high-risk familial predisposition to morbid obesity. Birth cohort from general population constituted the validation sample. For the discovery sample, 218 children with non-syndromic obesity and 190 control individuals were included. The validation sample was 653 children from two birth cohorts belonging to the INMA (Infancia y Medio Ambiente [Environment and Childhood] )project. 109 SNPs located in the genes FTO, SEC16B, BDNF, ETV5, SH2B1, GNPDA2, LYPLAL1, MSRA, TFAP2, KCTD15, MTCH2 and NEGR1, previously reported in association to body mass index (BMI) were analysed. For the validation sample, association between genome-wide data and BMI measurements between 3.5 and 5 years of age, were evaluated. The GRS includes six SNPs in the genes FTO, TFAP2B, SEC16B, ETV5 and SH2B1. The score distribution differs among cases and controls (P = 9.2 × 10(-14) ) showing a significant linear association with obesity (odds ratio [OR] per allele = 1.69; confidence interval [CI] 95% = 1.46-1.97; P = 4.3 × 10(-1) and area under the receiver operating characteristic curve [AUC] = 0.727; CI 95% = 0.676-0.778). The results were validated by the INMA cohort (OR per allele = 1.23 CI 95% = 1.03-1.48 and AUC = 0.601 CI 95% = 0.522-0.680). The use of our proposed genetic score provides useful information to determine those children who are susceptible to obesity. To improve the efficiency of clinical prevention and treatment of obesity, it is essential to design individualized based protocols in advance knowledge of the molecular basis of inherited susceptibility. Show less

Recent genome-wide association studies have identified a few single nucleotide polymorphisms (SNPs), which are associated with body mass index (BMI)/obesity. This study aimed to examine the identified associations among a population of Chinese children. Five SNPs (SEC16B rs10913469, SH2B1 rs4788102, PCSK1rs6235, KCTD15 rs29941, BAT2 rs2844479) were genotyped for a group of Chinese children (N = 2849, age range 6-18 years). A total of 1230 obese cases and 1619 controls with normal weight were identified based on the Chinese age- and sex-specific BMI references. Of five studied variants, only two (SEC16B rs10913469, SH2B1 rs4788102) were nominally associated with indices of adiposity and obesity risk in girls and only SEC16B rs10913469 in children at puberty (p < 0·05), while no statistical associations was found for three other variants (PCSK1rs6235, KCTD15 rs29941, BAT2 rs2844479). After false discovery rate (FDR) adjustment for multiple testing, none were statistically significant. Further analysis indicated that the genetic risk score (GRS) was associated with BMI, waist circumference and risk of obesity (defined by BMI) in girls, even after FDR adjustment for multiple testing. However, there was no statistical association of GRS with indices of adiposity and risk of obesity in children at puberty after multiple comparison correction. This study confirmed the synthetic effect of SNPs on the indices of adiposity and risk of obesity in Chinese girls, but failed to replicate the effect of five separate variants. We also did not found cumulative effect of SNPs in children at puberty. Show less

Birth weight reflects prenatal metabolic adaption and has been related to later-life obesity risk. This study aimed to evaluate whether birth weight modifies the effect of genetic susceptibility on obesity risk in young Chinese. We recruited 540 young (14-30 years) and obese patients (body mass index, BMI30 kg m(-2)), and 500 age- and sex-matched normal-weight healthy individuals (BMI<23 kg m(-2)). We genotyped 23 BMI-associated genetic variants identified from recent genome-wide association studies (GWAS) in Caucasians with European ancestry with minor allele frequency>0.05 in HapMap Han Chinese in Beijing, China. Six loci, including SEC16B, GNPDA2, BDNF, FTO, MC4R and TMEM160, were significantly associated with obesity risk, with odds ratio from 1.314 to 1.701. The 23 risk loci accounted for 6.38% of the genetic variance in obesity. We created two genetic risk scores (GRSs) by summing the risk alleles of all 23 (GRS1) and 6 obesity-associated (GRS2) genetic variants. Prediction of obesity was significantly improved (P<0.001) when the GRS1 and GRS2 were added to a model with age and gender, with improvement of discrimination for obesity by 0.8% and 2.7%, respectively. In addition, we found that the two GRSs interacted with birth weight in relation to obesity (Pinteraction<0.001). The genetic effect appeared to be more pronounced in individuals with normal range of birth weight (25-75%) than those with either low (<25%) or high (>75%) birth weight. We confirmed the associations of the single-nucleotide polymorphism tagging six loci reported in recent GWAS with obesity in young Chinese. Our data also suggest birth weight may significantly modify genetic susceptibility to obesity risk. Show less

Several studies have identified multiple obesity-associated loci mainly in European populations. However, their contribution to obesity in other ethnicities such as Mexicans is largely unknown. The aim of this study was to examine 26 obesity-associated single-nucleotide polymorphisms (SNP) in a sample of Mexican mestizos. 9 SNPs in biological candidate genes showing replications (PPARG, ADRB3, ADRB2, LEPR, GNB3, UCP3, ADIPOQ, UCP2, and NR3C1), and 17 SNPs in or near genes associated with obesity in first, second and third wave GWAS (INSIG2, FTO, MC4R, TMEM18, FAIM2/BCDIN3, BDNF, SH2B1, GNPDA2, NEGR1, KCTD15, SEC16B/RASAL2, NPC1, SFRF10/ETV5, MAF, PRL, MTCH2, and PTER) were genotyped in 1,156 unrelated Mexican-Mestizos including 683 cases (441 obese class I/II and 242 obese class III) and 473 normal-weight controls. In a second stage we selected 12 of the SNPs showing nominal associations with obesity, to seek associations with quantitative obesity-related traits in 3 cohorts including 1,218 Mexican Mestizo children, 945 Mexican Mestizo adults, and 543 Indigenous Mexican adults. After adjusting for age, sex and admixture, significant associations with obesity were found for 6 genes in the case-control study (ADIPOQ, FTO, TMEM18, INSIG2, FAIM2/BCDIN3 and BDNF). In addition, SH2B1 was associated only with class I/II obesity and MC4R only with class III obesity. SNPs located at or near FAIM2/BCDIN3, TMEM18, INSIG2, GNPDA2 and SEC16B/RASAL2 were significantly associated with BMI and/or WC in the combined analysis of Mexican-mestizo children and adults, and FTO locus was significantly associated with increased BMI in Indigenous Mexican populations. Our findings replicate the association of 8 obesity-related SNPs with obesity risk in Mexican adults, and confirm the role of some of these SNPs in BMI in Mexican adults and children. Show less

Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction  = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction  = 0.014 vs. n = 71,611, Pinteraction  = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction  = 0.003) and the SEC16B rs10913469 (Pinteraction  = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal. Show less

Genome-wide association studies have revealed several gene variants associated with obesity; however, only a few studies have further investigated their association with metabolic syndrome. We performed a study of eleven variants in/near genes TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R, and FTO in Czech adolescents and analysed their association with obesity, metabolic syndrome and related traits. Genotyping was performed in 1,443 adolescents aged 13.0-17.9 years. Anthropometric parameters, biochemical parameters and blood pressure were assessed. Metabolic syndrome was defined according to the International Diabetes Federation. The FTO rs9939609 variant was associated with overweight/obesity (OR 1.40, 95% CI 1.21-1.63, P < 0.001). The minor allele of TMEM18 rs7561317 was related to underweight (OR 1.78, 95% CI 1.14-2.79, P = 0.015). BDNF rs925946 and MC4R rs17782313 were associated with metabolic syndrome (OR 1.53, 95% CI 1.14-2.04, P = 0.005; 1.51, 95% CI 1.12-2.04, P = 0.009). The PCSK1 rs6235 variant was negatively related to increased blood glucose (OR 0.69, 95% CI 0.49-0.97, P = 0.040). In conclusion, the FTO variant was associated with overweight/obesity in Czech adolescents. Moreover, MC4R and BDNF variants increased the risk of metabolic syndrome, probably through their effect on abdominal obesity. The PCSK1 variant may have a protective role in the development of type 2 diabetes. Show less

Adipocytes hypertrophy is the main cause of obesity and its affliction such as type 2 diabetes (T2D). Since superparamagnetic iron oxide nanoparticles (SPIONs) are used for a wide range of biomedical/medical applications, we aimed to study the effect of SPIONs on 22 and 29 risk genes (Based on gene wide association studies) for obesity and T2D in human adipocytes. The mRNA expression of lipid and glucose metabolism genes was changed upon the treatment of human primary adipocytes with SPIONs. mRNA of GULP1, SLC30A8, NEGR1, SEC16B, MTCH2, MAF, MC4R, and TMEM195 were severely induced, whereas INSIG2, NAMPT, MTMR9, PFKP, KCTD15, LPL and GNPDA2 were down-regulated upon SPIONs stimulation. Since SEC16B gene assist the phagocytosis of apoptotic cells and this gene were highly expressed upon SPIONs treatment in adipocytes, it is logic to assume that SPIONs may play a crucial role in this direction, which requires more consideration in the future. Show less

Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10⁻⁸) near FTO (P = 3.72 × 10⁻²³), TMEM18 (P = 3.24 × 10⁻¹⁷), MC4R (P = 4.41 × 10⁻¹⁷), TNNI3K (P = 4.32 × 10⁻¹¹), SEC16B (P = 6.24 × 10⁻⁹), GNPDA2 (P = 1.11 × 10⁻⁸) and POMC (P = 4.94 × 10⁻⁸) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10⁻⁵ after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages. Show less

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci. Show less

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. 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 (N = 3502, 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. 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: OR = 1.29, 95%CI = 1.10-1.50, p = 0.001; MC4R rs17782313: OR = 1.27, 95%CI = 1.12-1.44, p = 1.32×10⁻⁴; GNPDA2 rs10938397: OR = 1.22, 95%CI = 1.09-1.37, p = 4.09×10⁻⁴; BDNF rs6265: OR = 1.20, 95%CI = 1.08-1.34, p = 8.86×10⁻⁴; GRS: OR = 1.25, 95%CI 1.16-1.34, p = 2.58×10⁻⁹) 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. 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. Show less

Most genome-wide association studies are confined to middle-aged populations. It is unclear whether associations between single nucleotide polymorphisms (SNPs) and obesity persist in old age. We aimed to relate 10 body mass index (BMI)-associated SNPs to weight, BMI, % fat, visceral and subcutaneous adipose tissue in Health ABC and AGES-Reykjavik comprising 4,846 individuals of European Ancestry, and 1,139 African Americans over age 65. SNPs were scaled using effect estimates from candidate SNPs. In Health ABC, a SNP near GNPDA2 was modestly associated with weight and SAT area (p = .008, p = .001). Risk score (sum of scaled SNPs) was associated with weight, BMI, and SAT area (p < .0001 for all), but neither GNPDA2 nor risk score was associated with weight, BMI, visceral adippose tissue, subcutaneous adipose tissue, or % fat in AGES-Reykjavik. In African Americans, a SNP near SEC16B was weakly associated with weight (p = .04). In this sample of older adults, no BMI-associated SNPs were associated with weight or adiposity. Show less

Longitudinal growth associations with genetic variants identified for adult BMI may provide insights into the timing of obesity susceptibility. The objective was to explore associations of known BMI loci with measures of body size from birth to adulthood. A total of 2537 individuals from a longitudinal British birth cohort were genotyped for 11 genetic variants robustly associated with adult BMI (in/near FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, ETV5, SEC16B, SH2B1, and MTCH2). We derived an obesity-risk-allele score, comprising the sum of BMI-increasing alleles in each individual, and examined this for an association with birth weight and repeated measures of weight, height, and BMI SD scores (SDS) at 11 time points between ages 2 and 53 y. The obesity-risk-allele score showed borderline significant association with birth weight (0.019 SDS/allele; P = 0.05) and was more clearly associated with higher weight and BMI at all time points between ages 2 and 53 y; the strongest associations with weight occurred at ages 11 and 20 y (both 0.056 SDS/allele). In longitudinal analyses, the score was positively associated with weight gain only between birth and 11 y (0.003 SDS/allele per year; 95% CI: 0.001, 0.004; P = 0.001). The risk-allele score was associated with taller height at 7 y (0.031 SDS/allele; P = 0.002) and greater height gains between 2 and 7 y (0.007 SDS/allele per year; P < 0.001), but not with adult height (P = 0.5). The combined effect of adult obesity susceptibility variants on weight gain was confined to childhood. These variants conferred a faster tempo of height growth that was evident before the pubertal years. Show less

In populations of East Asian descent, we performed a replication study of loci previously identified in populations of European descent as being associated with obesity measures such as BMI and type 2 diabetes. We genotyped 14 single nucleotide polymorphisms (SNPs) from 13 candidate loci that had previously been identified by genome-wide association meta-analyses for obesity measures in Europeans. Genotyping was done in 18,264 participants from two general Japanese populations. For SNPs showing an obesity association in Japanese individuals, we further examined diabetes associations in up to 6,781 cases and 7,307 controls from a subset of the original, as well as from additional populations. Significant obesity associations (p < 0.1 two-tailed, concordant direction with previous reports) were replicated for 11 SNPs from the following ten loci in Japanese participants: SEC16B, TMEM18, GNPDA2, BDNF, MTCH2, BCDIN3D-FAIM2, SH2B1-ATP2A1, FTO, MC4R and KCTD15. The strongest effect was observed at TMEM18 rs4854344 (p = 7.1 × 10(-7) for BMI). Among the 11 SNPs showing significant obesity association, six were also associated with diabetes (OR 1.05-1.17; p = 0.04-2.4 × 10(-7)) after adjustment for BMI in the Japanese. When meta-analysed with data from the previous reports, the BMI-adjusted diabetes association was found to be highly significant for the FTO locus in East Asians (OR 1.13; 95% CI 1.09-1.18; p = 7.8 × 10(-10)) with substantial inter-ethnic heterogeneity (p = 0.003). We confirmed that ten candidate loci are associated with obesity measures in the general Japanese populations. Six (of ten) loci exert diabetogenic effects in the Japanese, although relatively modest in size, and independently of increased adiposity. Show less

The origin of peroxisomes has long been disputed. However, recent evidence suggests that peroxisomes can be formed de novo from the endoplasmic reticulum (ER) in yeast and higher eukaryotes. Sec16A and Sec16B, mammalian orthologs of yeast Sec16, are scaffold proteins that organize ER exit sites by interacting with COPII components. We recently demonstrated that Sec16B, but not Sec16A, regulates the transport of peroxisomal biogenesis factors from the ER to peroxisomes in mammalian cells. The C-terminal region of Sec16B, which is not conserved in Sec16A, is required for this function. The data suggest that Sec16B in ER areas other than ER exit sites plays this role. Our findings provide an unexpected connection between at least part of the COPII machinery and the formation of preperoxisomal vesicles at the ER, and offer an explanation of how secretory and peroxisomal trafficking from the ER are distinguished. Show less

The endoplasmic reticulum (ER) represents the entry point into the secretory pathway and from here newly synthesized proteins and lipids are delivered to the Golgi. The selective cargo export from the ER is mediated by COPII-assembly at specific sites of the ER, the so-called transitional ER (tER). The peripheral membrane protein Sec16, first identified in yeast, localizes to transitional ER and plays a key role in organization of these sites. Sec16 defines the tER and is thought to act as a scaffold for the COPII coat assembly. In humans two isoforms of Sec16 are present, the larger Sec16A and the smaller Sec16B. Nevertheless, the functional differences between the two isoforms are ill-defined. Here we describe characterization of the localization and dynamics of Sec16B relative to Sec16A, provide evidence that Sec16B is likely a minor or perhaps specialized form of Sec16, and that it is not functionally redundant with Sec16A. Show less

Obesity is a well-established risk factor for endometrial cancer, the most common gynecologic malignancy. Recent genome-wide association studies (GWAS) have identified multiple genetic markers for obesity. The authors evaluated the association of obesity-related single nucleotide polymorphisms (SNPs) with endometrial cancer using GWAS data from their recently completed study, the Shanghai Endometrial Cancer Genetics Study, which comprised 832 endometrial cancer cases and 2,049 controls (1996-2005). Thirty-five SNPs previously associated with obesity or body mass index (BMI; weight (kg)/height (m)(2)) at a minimum significance level of ≤5 × 10(-7) in the US National Human Genome Research Institute's GWAS catalog (http://genome.gov/gwastudies) and representing 26 unique loci were evaluated by either direct genotyping or imputation. The authors found that for 22 of the 26 unique loci tested (84.6%), the BMI-associated risk variants were present at a higher frequency in cases than in population controls (P = 0.0003). Multiple regression analysis showed that 9 of 35 BMI-associated variants, representing 7 loci, were significantly associated (P ≤ 0.05) with the risk of endometrial cancer; for all but 1 SNP, the direction of association was consistent with that found for BMI. For consistent SNPs, the allelic odds ratios ranged from 1.15 to 1.29. These 7 loci are in the SEC16B/RASAL, TMEM18, MSRA, SOX6, MTCH2, FTO, and MC4R genes. The associations persisted after adjustment for BMI, suggesting that genetic markers of obesity provide value in addition to BMI in predicting endometrial cancer risk. Show less

Thirty-two common variants associated with body mass index (BMI) have been identified in genome-wide association studies, explaining ∼1.45% of BMI variation in general population cohorts. We performed a genome-wide association study in a sample of young adults enriched for extremely overweight individuals. We aimed to identify new loci associated with BMI and to ascertain whether using an extreme sampling design would identify the variants known to be associated with BMI in general populations. From two large Danish cohorts we selected all extremely overweight young men and women (n = 2,633), and equal numbers of population-based controls (n = 2,740, drawn randomly from the same populations as the extremes, representing ∼212,000 individuals). We followed up novel (at the time of the study) association signals (p<0.001) from the discovery cohort in a genome-wide study of 5,846 Europeans, before attempting to replicate the most strongly associated 28 SNPs in an independent sample of Danish individuals (n = 20,917) and a population-based cohort of 15-year-old British adolescents (n = 2,418). Our discovery analysis identified SNPs at three loci known to be associated with BMI with genome-wide confidence (P<5×10(-8); FTO, MC4R and FAIM2). We also found strong evidence of association at the known TMEM18, GNPDA2, SEC16B, TFAP2B, SH2B1 and KCTD15 loci (p<0.001), and nominal association (p<0.05) at a further 8 loci known to be associated with BMI. However, meta-analyses of our discovery and replication cohorts identified no novel associations. Our results indicate that the detectable genetic variation associated with extreme overweight is very similar to that previously found for general BMI. This suggests that population-based study designs with enriched sampling of individuals with the extreme phenotype may be an efficient method for identifying common variants that influence quantitative traits and a valid alternative to genotyping all individuals in large population-based studies, which may require tens of thousands of subjects to achieve similar power. Show less

Genome-wide association studies have identified novel BMI/obesity associated susceptibility loci. The purpose of this study is to determine associations with overweight, obesity, morbid obesity and/or general adiposity in a Danish population. Moreover, we want to investigate if these loci associate with type 2 diabetes and to elucidate potential underlying metabolic mechanisms. 15 gene variants in 14 loci including TMEM18 (rs7561317), SH2B1 (rs7498665), KCTD15 (rs29941), NEGR1 (rs2568958), ETV5 (rs7647305), BDNF (rs4923461, rs925946), SEC16B (rs10913469), FAIM2 (rs7138803), GNPDA2 (rs10938397), MTCH2 (rs10838738), BAT2 (rs2260000), NPC1 (rs1805081), MAF (rs1424233), and PTER (rs10508503) were genotyped in 18,014 middle-aged Danes. Five of the 15 gene variants associated with overweight, obesity and/or morbid obesity. Per allele ORs ranged from 1.15-1.20 for overweight, 1.10-1.25 for obesity, and 1.41-1.46 for morbid obesity. Five of the 15 variants moreover associated with increased measures of adiposity. BDNF rs4923461 displayed a borderline BMI-dependent protective effect on type 2 diabetes (0.87 (0.78-0.96, p = 0.008)), whereas SH2B1 rs7498665 associated with nominally BMI-independent increased risk of type 2 diabetes (1.16 (1.07-1.27, p = 7.8×10(-4))). Associations with overweight and/or obesity and measures of obesity were confirmed for seven out of the 15 gene variants. The obesity risk allele of BDNF rs4923461 protected against type 2 diabetes, which could suggest neuronal and peripheral distinctive ways of actions for the protein. SH2B1 rs7498665 associated with type 2 diabetes independently of BMI. Show less

Visceral fat accumulation has an important role in increasing morbidity and mortality rate by increasing the risk of developing several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of obesity have been identified by genome-wide association studies in Caucasian populations. We genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography (CT) for measuring visceral fat area (VFA) and subcutaneous fat area (SFA), for the following single-nucleotide polymorphisms (SNPs): NEGR1 rs2815752, SEC16B rs10913469, TMEM18 rs6548238, ETV5 rs7647305, GNPDA2 rs10938397, BDNF rs6265 and rs925946, MTCH2 rs10838738, SH2B1 rs7498665, MAF rs1424233, and KCTD15 rs29941 and rs11084753. In the additive model, none of the SNPs were significantly associated with body mass index (BMI). The SH2B1 rs7498665 risk allele was found to be significantly associated with VFA (P=0.00047) but not with BMI or SFA. When the analysis was performed in men and women separately, no significant associations with VFA were observed (P=0.0099 in men and P=0.022 in women). None of the other SNPs were significantly associated with SFA. Our results suggest that there is a VFA-specific genetic factor and that a polymorphism in the SH2B1 gene influences the risk of visceral fat accumulation. Show less