| [Background]With the development of economy and the change of lifestyles and dietary pattern, obesity is a growing global public health issue. Globally, in2010, the number of overweight and obese children under the age of five was estimated to be over42million with about35million living in developing countries. Childhood obesity is prone to obesity in adolescence which is likely to stay obese into adulthood. The World Health Organization projected that by2015, approximately2.3billion adults will be overweight and more than700million will be obese. In China, the overweight and obesity is growing with a worrying speed too. Based on current research reports, in our country, the rate of overweight is about24.15%-41.04%, and the rate of obesity is about4.6%-23.75%. Although there is difference in the rates of overweight and obesity in different areas of China, the same is that the rates are high. And the issue has become ignoreless.Overweight and obesity are related to many diseases. Obesity plays an important role in the pathogenesis of type I diabetes mellitus, hypertension, cardiovascular disease and some cancers. Obesity impedes the psychological and behavior development of children, and suppresses the development of potentiality. Meanwhile, overweight and obesity could lead to heavy economic burden to the families and the society. Overweight and obesity has become to one of the global serious public health issues. A clearer understanding of the determinants of obesity can contribute to improved management and prevention measures and to control the "epidemic" of obesity. Because obesity plays an important role in the pathogenesis of many diseases, controlling the epidemic of obesity has huge public health significance.As a complicated condition, obesity happens and develops with the participation of many genes and factors, and do not conform to Mendelian inheritance. Based on current studies, the happen and development of obesity is related to genetic factors, environmental factors, early-life experiences, biological factors and so on. Foetus origin theory or development origin theory is the rationale of the association of early-life experiences, such as birth weight, with later overweight and obesity. Foetus origin theory or development origin theory bases on this concept:Early-life experiences in uterus may induce permanent changes in physiologic function programming the long-term regulation of energy balance. This subsequently may impact obesity risk in the later life. Gene-wide association studies have discovered more than hundred loci related to obesity, but they only explain2%genetic variation of BMI. The inconsistency between degree of obesity heritability and genetic variation may be caused by interaction of gene loci, or interaction of gene with environmental factors. It is reported that although the effect of individual gene polymorphism on obesity is weak, the effect of joint action of many genes and joint action of genes and environmental factors is strong enough to increase the risk of obesity. There is inconsistency among the results of recent studies on the association of gene polymorphism with obesity, which may be due that the interactions of early-life experiences, gene factors and environmental factors were not considered in the studies. Exploration to the occurrence and development of obesity from the actions of early-life experiences, gene factors, environmental factors and their interactions is important to clear cut comprehensive understanding of obesity.[Object]We armed to explore the effect of high birth weight (HBW) on overweight and obesity in adolescence, to screen gene polymorphism markers related to overweight and obesity in Chinese adolescence and rich the biological markers of susceptibility to overweight and obesity in Chinese adolescence, and to explore the interaction among HBW, genetic factors and environmental factors. By this study, we tried to understand and explain the mechanism underlying the overweight and obesity in adolescence, and provide a scientific basis for identifying the population at risk of overweight and obesity and improving the prevention measures.[Methods]We conducted a longitudinal study of the HBW birth cohort in Wuxi, China. The birth cohort included3230live-born neonates born in1993,1994, and1995in three districts (Jiangyin, Huishan and Xishan) of Wuxi. In the birth cohort, subjects with a BW≥4000g were selected as the exposed group. For each exposed subject, one non-exposed subject with a BW of2500-3999g, matched by year of birth, sex, and type of institute at birth was chosen. We excluded subjects who were stillbirths, those who died before their12th birthday, those who had major congenital malformations, and those who moved outside of the study area before the scheduled follow-up. The first follow-up was performed between1October2005and1February2007. The present study performed between1October2010and1April2012was the second follow-up.Baseline data (gestational and perinatal data) including maternal age, parity, body mass index (BMI) before pregnancy, date of the last menstrual period, pregnancy complications, infant’s date of birth, birth weight and so on were obtained from the records maintained by the local Maternal and Children Health Bureaus. There were four parts in the second follow-up:questionnaire investigation, physical examination, detection of biochemical markers related to metabolism, genotype identification of gene loci related to metabolism.Questionnaire investigation included the investigation to the selected students and the investigation to their parents. Data on socio-demography, current household income, physical activity, and dietary habits were collected face-to-face by trained nurses. The subjects’height, weight, blood pressure, waist circumference, and hip circumference were measured according to the methods recommended by WHO.After the follow-up, nest case-control study was performed. The overweight and obesity (excluding the morbid obesity) in the cohort were chosen as cases and control with normal weight matched by age and sex were chosen. Blood sample was extracted from each case and control with empty stomach and separated as soon as possible. Plasma concentrations of cholesterol, triglycerides, HDL, apoprotein A1, apoprotein B, glucose, insulin, C petide and leptin were measured. DNA was abstracted with Whole Genomic DNA Extraction Kit. Then the genotypes of the loci of leptin receptor gene rsl46442768, rs1137100and rs8179183, UCP1gene rs3811791and rs1800592, PPARδ gene rs2016520, FTO gene rs9939609、rs1558902and rs8050136, MC4R gene rs17782313were identified using Matrix assisted1Laser desorption ionization time-of-flight mass spectrometry or gene sequencing.All the data were double entered and checked using the software EpiData3.1. All analyses were performed using Statistical Analysis Software version9.2, SHEsis Online Software and MDR Software.[Results]1. Characteristics of the SubjectsThere were2302subjects participating the second follow-up among3230original HBW cohort, and the rate of follow-up was71.27%. There were1156in the exposed group and1128in the non-exposed group. The age of the subjects was between15and18years in the second follow-up, among whom65.25%were boys. There were278overweight or obesity, and the rate of overweight/obesity was12.08%. The rate of overweight/obesity was12.18%in boys, and11.88%in girls. The rates of overweight/obesity for the age of15,16,17, and18were12.63%,12.02%,10.50%and14.69%, respectively.2. Associations between HBW and adolescent overweight/obesity, waist circumference, hip circumference, abdominal obesity, blood pressure and biochemical markers related to metabolismThe rate of overweight/obesity was14.88%in the exposed group and9.25%in the non-exposed group, and there was statistical difference between the two group (P＜0.05). HBW increased the risk of adolescent overweight/obesity with a RR=1.61and a95%CI=1.28-2.02. After adjusting for sex, age and incoming/month, the association was still found (P＜0.05).The means of chest circumference, waist circumference and hip circumference were83.06cm,74.50cm, and89.48cm in the exposed group, and82.02cm,73.11cm,88.16cm in the non-exposed group. There was statistical difference between the two group (P＜0.05), and the chest circumference, waist circumference and hip circumference were significantly higher in the exposed group than in the non-exposed group. The means of waist-to-hip ratio (WHR) were both0.83in the exposed group and the non-exposed group, and no statistical difference was found between the two group (P>0.05).The rate of abdominal obesity was15.83%in the exposed group and9.77%in the non-exposed group, and there was statiscally difference between the two group (P＜0.0001). HBW increased the risk of adolescent abdominal overweight/obesity with a RR=1.62and a95%CI=1.30-2.02. After adjusting for sex, the association was still found (P＜0.05).The rate of higher blood pressure was12.98%in the exposed group and12.57%in the non-exposed group. No statistical difference was found between the two group (P>0.05).No statistical differences in plasma concentrations of cholesterol, triglycerides, HDL, apoprotein A1, apoprotein B, glucose, insulin, C petide and leptin was found between the exposed group and the non-exposed group by wilcoxon rank test (P>0.05). The rates of insulin resistance, damage of islet cell function, insulin abnormality and C peptide abnormality were16.76%,0.58%,5.20%and2.31%in the exposed group and17.90%,0.44%,3.93%and2.62%in the non-exposed group. No statistical differences in insulin resistance, damage of islet cell function, insulin abnormality and C peptide abnormality was found between the two group (P>0.05).3. The environmental factors influencing adolescent overweight/obesity and their interactionsBy logistic stepwise regression analysis, it was found that HBW, only one child, higher education level for mother, eating very full, eating puffed food often, eating snack food often, one parent being obese or both obese increased the risk of adolescent overweight/obesity; on the other hand, eating slowly, little appetite, objecting obesity oneself, mother’s objection to obesity, purchasing food according to the health requirement decreased the risk of adolescent overweight/obesity.The subjects were clustered using latent class analysis. Among the subjects,267belonged to unhealthy diet favorite,56to unhealthy diet habit,1731to healthy diet habit,247to common diet habit, and the data on diet for1person was lack.By MDR analysis, it was found that there was first-order interaction between HBW and diet favorite, second-order interaction among HBW, diet favorite and parents being obese, third-order interaction among HBW, diet favorite, age and attitude to obesity. First-order interaction was found between HBW and diet favorite (OR=0.37,95% CI=0.19,0.69) based on the multiplicative model. But based on the additive model, adolescents with a HBW and unhealthy dietary favorite had no increased risk of overweight/obesity (RERI=-2A5,95%CI=-4.55,0.26). So there may be no biological interaction between HBW and unhealthy dietary favorite.By logistic stepwise regression analysis, it was found that HBW, older, drinking soft beverage often, eating meat often, eating snack food often, one parent being obese or both obese, longer sleeping increased the risk of adolescent abdominal obesity; on the other hand, higher education level for mother, little appetite, objectting obesity oneself, purchasing food according to the health requirement decreased the risk of adolescent abdominal obesity.By MDR analysis, it was found that there was first-order interaction between HBW and sleep lenght, second-order interaction among attitude to obesity, age and sleep lenght, third-order interaction among attitude to obesity, age, mother’education level and parents obesity. First-order interaction was found between HBW and sleep lenght (OR=0.51,95%CI=0.28,0.95) based on the multiplicative model. But based on the additive model, adolescents with a HBW and longer sleeping had no increased risk of abdominal obesity (RERI=-0.91,95%CI=-2.57,0.75). So there may be no biological interaction between HBW and sleep lenght.4. The genetic factors influencing adolescent overweight/obesity and their interactionsIn the present study, the genotypes in leptin receptor gene rs146442768locus, rs1137100locus and rs8179183locus, UCP1gene rs3811791locus and rs1800592locus, PPARδ gene rs2016520locus, FTO gene rs9939609locus, rs1558902locus and rs8050136locus, MC4R gene rs17782313locus were detected. No mutation was found in leptin receptor gene rs146442768locus. Hetetozygous mutation rates were high and homozygous mutation rates were low in leptin receptor gene rs1137100locus and rs8179183locus, UCP1gene rs3811791locus, PPARδ gene rs2016520locus, FTO gene rs9939609locus, rs1558902locus and rs8050136locus, MC4R gene rs17782313locus. But the hetetozygous and homozygous mutation rates were both high in the rs1800592locus, which were47.73%and26.01%, respectively. Comparing with GG genotype in leptin receptor gene rs8179183, GC/CC genotype increased the risk of adolescent overweight/obesity with an OR=2.56and a95%CI=1.26-5.18. Comparing with TT genotype in FTO gene rs9939609, TA/AA genotype increased the risk of adolescent overweight/obesity with an OR=1.66and a95%CI=1.03-2.68. Comparing with TT genotype in FTO gene rs1558902, TA/AA genotype increased the risk of adolescent overweight/obesity with an OR=1.61and a95%CI=1.00-2.60. Comparing with CC genotype in FTO gene rs8050136, CA/AA genotype increased the risk of adolescent overweight/obesity with an OR=1.65and a95%CI=1.02-2.65. No associations were found between adolescent overweight/obesity and SNP polymorphism in other gene loci (leptin receptor gene rsl46442768and rs1137100, UCP1gene rs3811791and rs1800592, PPARδ gene rs2016520, MC4R gene rs17782313). By linkage disequilibrium tests, it was found that rs9939609, rs1558902and rs8050136loci in FTO gene were complete linkage equilibrium. TTC haplotype and AAA haplotype were associated with adolescent overweight/obesity (P＜0.05). The risk of overweight/obesity in adolescents with TTC haplotype may be low, and those with AAA haplotype may be high. AC haplotype in leptin receptor gene was related to adolescent overweight/obesity (P=0.0080), and AC haplotype increased the risk of overweight/obesity.When both environmental factors and genetic factors were brought into the logistic regression model, it was found that mutation in FTO gene rs9939609locus, only one child, higher education level for mother, well appetite, eating snack food often, parents being obese increased the risk of adolescent overweight/obesity, and eating slowly, disapprove of obesity oneself decreased the risk of adolescent overweight/obesity.It was found that adolescent waist circumference was related to the SNP polymorphisms in the leptin receptor gene rs8179183locus, FTO gene rs9939609locus and rs8050136locus (P＜0.05); adolescent abdominal obesity was related to the SNP polymorphisms in the leptin receptor gene rs8179183locus, FTO gene rs9939609locus, rs1558902locus and rs8050136locus (P＜0.05); AC haplotype in leptin receptor gene, TTC haplotype and AAA haplotype in FTO gene were associated with adolescent abdomental obesity (P＜0.05); adolescent systolic pressure was related to the SNP polymorphisms in leptin receptor gene rs1137100locus and rs8179183locus (P＜0.05); adolescent diastolic pressure was related to the SNP polymorphisms in the FTO gene rs9939609locus and rs8050136locus (P＜0.05); adolescent plasma concentrations of glucose was related to the SNP polymorphism in UCP1gene rs3811791locus (P＜0.05); adolescent plasma concentrations of apolipoprotein B was related to the SNP polymorphism in leptin receptor gene rs8179183locus (P＜0.05); adolescent plasma concentrations of C peptide was related to the SNP polymorphisms in UCP1gene rs3811791locus and MC4R gene rs17782313locus (P＜0.05).No statistical differences in hip circumference, WHR, sebum thickness in upper arm and back between the different genotypes in the loci of leptin receptor gene rs146442768, rs1137100and rs8179183, UCP1gene rs3811791and rs1800592, PPARδ gene rs2016520, FTO gene rs9939609, rs1558902and rs8050136, MC4R gene rs17782313(P>0.05).No interactions were found among the SNP polymorphisms in the loci of leptin receptor gene rsl46442768, rs1137100and rs8179183, UCP1gene rs3811791and rs1800592, PPARδ gene rs2016520, FTO gene rs9939609, rs1558902and rs8050136, MC4R gene rs17782313by the MDR analysis or the interaction analysis based on the multiplicative model or the additive model.5. Interaction among environmental and genetic factors on adolescent overweight/obesityThe interaction graph of MDR model showed that there may be interactions between age and SNP polymorphism in the UCP1gene rs3811791locus, between diet favorite and SNP ploymorphism in the FTO gene rs9939609locus, between physical activity time and sitting time. Based on the multiplicative model, interaction was found between physical activity time and sitting time (OR=1.99,95%CI=1.18,3.37), but no interactions were found between age and SNP polymorphism in the UCP1gene rs3811791locus, and between diet favorite and SNP ploymorphism in the FTO gene rs9939609locus (P>0.05). After adjusting for other environmental and genetic factors, interaction was found between age and SNP polymorphism in the UCP1gene rs3811791locus (OR=2.00,95%CI=1.20,3.36). Based on the additive model, interaction was found between physical activity time and sitting time. Adolescents with less physical activities and long sitting time could increase the risk of overweight/obesity (OR=1.86,95%CI=1.32,2.62; RERI=0.92,95%CI=0.35,1.48). Because of the interaction, the extraneous risk of overweight/obesity in the adolescents with little physical activities and long sitting time increased0.92time. Among the overweight/obesity with less physical activities and long sitting time,50%was ascribed to the effect of the interaction between physical activity time and sitting time (AP=50%).6. The mechanism underlying the association of HBW with adolescent overweight/obesityThe SNP ploymorphisms in leptin receptor gene rs8179183locus, FTO gene rs9939609locus, rs1558902locus and rs8050136locus were related to adolescent overweight/obesity (P＜0.05), but were not related to birth weight (P>0.05). The SNP ploymorphism in MC4R gene rs17782313locus was related to high birth weight (P＜0.05). Comparing with TT genotype, TC/CC genotype increased the risk of HBW with a OR=1.53and a95%CI=1.01-2.33. But it was not found that the SNP ploymorphism was related to adolescent overweight/obesity (P>0.05).[Conclusions]1. The risk of overweight/obesity in the adolescence with HBW may be increased. Birth weight may be related to adolescent chest circumference, waist circumference, hip circumference and abdominal obesity, but not related to adolescent blood pressure and biochemical markers related to metabolism.2. The environmental factors related to adolescent overweight/obesity may include HBW, only one child, education level for mother, eating very full, eating speed, appetite, puffed food intake, snack food intake, attitude to obesity oneself, mother’s attitude to obesity, purchasing food according to healthy requirement and parents obesity. There may be a negative multiplicative interaction between HBW and diet favorite. In other words, the risk of overweight/obesity in the adolescence with HBW and unhealthy diet favorite is lower than the sum of the risks caused by HBW and unhealthy diet favorite respectively.3. The SNP polymorphisms in leptin receptor gene rs8179183locus, FTO gene rs9939609locus, rs1558902locus and rs8050136locus may be related to adolescent overweight/obesity. The rs9939609, rs1558902and rs8050136loci in FTO gene were complete linkage equilibrium. TTC haplotype and AAA haplotype in FTO gene and AC haplotype in leptin receptor gene were associated with adolescent overweight/obesity. There may be no interaction among these SNP polymorphisms.4. There may be interaction between physical activity time and sitting time.5. The SNP polymorphisms in the loci of leptin receptor gene rs146442768, rs1137100and rs8179183, UCP1gene rs3811791and rs1800592, PPAR8gene rs2016520, FTO gene rs9939609、rs1558902and rs8050136, MC4R gene rs17782313are not the common genetic background of HBW and overweight/obesity. They do not play a role in the association of HBW and adolescent overweight/obesity. |
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