Association Studies Between The Single-nucleotide Polymorphism Of FTO Gene And Obesity In Chinese Han Children/Adolescents

Backgrounds and ObjectivesThe prevalence of obesity in children and adolescents has increased significantly over the past few decades, and it has becoming a severe global issue increasingly. With the change of living environment,(e.g. low level of physical activity, excessive energy intaken, sedentary lifestyle and so on) the prevalence of childhood obesity increases greatly. As is known, obesity could cause many related chronic diseases, such as cardiovaseular diseases, dyslipoproteinemia, hypertension, type2diabetes, and even some cancers. In addition, obesity leads to enormous social and economic burden.As other chronic disease, obesity is one of the most common metabolic disorders; it has a multi-factorial etiology involving complex interplay of environmental exposures and genetic susceptibility. Genetic and environmental factors play an important role in the emergence and development of obesity. Genetic factors increase the susceptibility to obesity. However, even in the presence of genetic factors, obesity is the interactive result of various environmental factors and lifestyle. Research on the relationship between genetic and environmental factors and obesity is significant in the prevention and control of childhood obesity.Recently, Genome-Wide Association Study put researches of obesity, metabolic syndrome, cancers and other important disease to a new level, and identified a group of loci associated with obesity. Among those genes; FTO explained the largest variation of obesity and BMI. Fat mass and obesity associated (FTO) gene is the first obesity-related gene discovered by large-scale GWAS. The human FTO gene is located on16q12.2,400kb length, consisting of nine exons and all coding protein. FTO gene is widely expressed in fetal and adult tissues, and highest expression in brain tissue, which is a key component of the control center of energy balance. Data shows that common variation in the FTO gene may lead the expression increased or disorders. People who carrying the risk allele will be obesity caused by excessive ingestion rather than changing the energy consumption. Cecil and colleagues report that the A allele of the FTO rs9939609gene variant, which has been linked with obesity, is also associated with increased levels of physical activity and ingestion in children. No differences in resting energy expenditure were observed. The association between the risk A allele and BMI was explained by a relative overconsumption of food.Although, the association of FTO genetic variants rs9939609T>A SNP with obesity and BMI was unequivocally replicated in European and Hispanic populations, these associations were controversial with regard to Asian populations There are reports supporting that the FTO gene has an important genetic effect on body mass index (BMI) and risk of obesity in Asian, but the conclusions were inconsistent. Furthermore, the mechanism of obesity is unclear. It is still need more repeatability research to verify the association between FTO gene and obesity in Chinese population.Its still need replicated studies on the associations of FTO rs9939609with obesity and obesity-related metabolic traits in Chinese population, as well as its interaction with environmental factors, to explore the possible pathway of FTO gene’s association with obesity. At the same time, further research on the relationship of genetic and environmental factors is of great significance in the prevention and control of obesity.Objective The objective of the study is to investigate whether FTO variants are associated with Chinese Han children and adolescents, to screen out of obesity-related SNPs makers, to enrich and complement the signs of genetic susceptibility.MethodsThe study population consisted of4000unrelated individuals, coming from Nanning, Tianjin, Beijing, Chongqing and Hangzhou. The age is ranging from7to18years. We conducted a case-control study to investigate the association between FTO variants and obesity in Chinese Han children and adolescents. Exclusion criteria include chronic disease, uncooperative or lack of information.1400obesity children who were diagnosed by BMI classification standards and2600obesity-free controls(study I:500/500, study Ⅱ:900/2100). were recruited in this study. The survey includes a questionnaire, medical examination, anthropometric measurement, and blood collection. After the written informed consent was obtained from the study subjects, a face-to-face interview was conducted by trained interviewers using a structured questionnaire including demographic characteristics (e.g., age, sex), lifestyle habits (e.g., diet habits, taste), medical history, family history of obesity. Additionally, with the permission of the subjects,5ml venous blood sample was collected after interview and the genomic DNA was isolated from peripheral blood samples. A comprehensive SNP selection was applied for FTO gene. There are24SNPs selected in total. Genotyping for the selected genetic polymorphisms was performed using SNPScan in Gene-sky Biotechnology Co. Ltd. Shanghai, and988were successfully genotyping.Excel2007and Epidata13.1were used for data entry and SPSS16.0for Windows, Plink-1.07-doc, HaploView and R for Windows2.14.0were used for data analysis. Multiple statistical methods including1-Sample K-S normality test, t test,%2test, Kruskal-Wallis test, trend test, Logistic regression, crossover analysis, were applied to explore the major and interactive effects of the genetic polymorphisms of FTO gene and lifestyle-related factors on obesity risk. To correct for multiple comparisons, false discovery rate (FDR) approach was used.ResultsThere was no significant difference between the cases and controls in terms of age and sex in both studies. After adjusted for sex and age, SNP rs9939609(P=0.002), rs7209790(P=0.018) and rs11644943(P=0.023) were significantly associated with obesity in Chinese Han children and adolescents in additive model. In addition, after adjusted for sex and age, SNP rs9939609was significantly increased the risk of obesity in Chinese Han children and adolescents in dominant model,(study Ⅰ:OR=1.57,95%CI:1.17-2.11, P=0.002; study Ⅱ:OR=1.57,95%CI:1.34-1.85; P<0.0001; combined study:(OR=1.56;95%CI:1.36-1.78; P<0.0001), while rs7209790(OR=3.76,95%CI:1.24-11.43; P=0.012) and rs11644943(OR=0.16,95%CI:0.04-0.72; P=0.017) were also significantly associated with obesity in Chinese Han children and adolescents in recessive model. However, there were no statistical significant associations between other21SNPs and children obesity.After adjusted for sex and age, risk AA allele of SNP rs9939609were significantly associated with BMI(P=0.005),waist(P=0.02),hip(P=0.05),and diet habit(P=0.03); risk GG allele of SNP rs7206790were significantly associated with BMI(P=0.007), weight(P=0.005), waist(P=0.05),hip(P=0.01),and Systobic blood pressure(P=0.04); rs11644943may significantly affect the taste(P=0.02). However, there were no statistical significant associations between other SNPs and obesity-related quantitative traits in study Ⅰ. While in study Ⅱ, we found that risk AA allele of SNP rs9939609were significantly associated with BMI(P<0.0001), waist(P<0.0001), hip(P=0.0003), SBP(P<0.0001),TG(P=0.007),LDLC(P=0.01), and HDLC(P=0.0002); risk GG allele of SNP rs7206790were significantly associated with BMI(P=0.007), weight(P=0.005), waist(P=0.05), hip(P=0.01), and Systobic blood pressure(P=0.04); rsl1644943may significantly affect the taste(P=0.02).In combined study, it is consistent with study Ⅰ and in study Ⅱ. After analysis of haplotypes of24SNPs in FTO gene,we found that the haplotype GG was associated with a significantly increased risk of obesity (OR=1.39,95%CI:1.07-1.81;P=0.02),while the haplotype GTA was associated with a significantly increased risk of obesity (OR=1.65,95%CI:1.24-2.19;P=0.001), no significant was observed between other haplotypes of FTO and obesity in Chinese Han children and adolescents.Significant gene-environment interaction was observed between FTO polymorphisms rs9939609and diet habit (OR=3.63,95%CI:1.89-7.01; P<0.001); We also found that there was Significant gene-environment interaction between rs9939609and taste (OR=5.38,95%CI:2.64-10.97; P<0.001). No significant gene-environment interaction was observed between other FTO polymorphisms and lifestyles.Conclusions1. To our knowledge, our study has replicated and confirmed the association of SNP rs9939609with both BMI and obesity in Chinese Han children and adolescents. Meanwhile, we found that rs9939609, rs7206790and rs11644943were associated with’ weight, waist and hip.2. The interaction of SNP rs9939609and lifestyle factors (e.g. diet habit, taste) increase the risk of obesity in Chinese Han children and adolescents, which contributes to our understanding of the etiology of obesity.