Objective: The present study aimed to prospectively validate whether the single nucleotide polymorphisms (SNPs) in obesity-related genes were associated with change in body mass index (BMI) and obesity status during childhood. Methods: Based on the Beijing Child and Adolescent Metabolic Syndrome study (BCAMS), which was initiated between April and October in 2004, we conducted a follow-up study among 1 624 children aged 6 to 11 years old with genetic data in December 2010. A total of 777 children (246 obese and 531 non-obese) were reassessed for BMI. Z-score of BMI was used to standardize for age and sex. The changes in BMI Z-score during follow up were calcnlated SNPs were genotyped by quantitative Real-time PCR (rs9939609, rs6499640, rs7138803, rs1805081, rs17782313, rs6265, rs10938397, rs6235, rs29941, rs2844479, rs10913469 and rs4788102). Overweight and obesity were diagnosed by the age-and sex-specific BMI cutoffs recommended by the International Obesity Task Force. A multilocus genetic risk score for BMI was calculated as the simple sum of alleles of all the SNPs associated with BMI. Linear regression models and logistic regression models were performed to assess the associations of change in BMI Z-score and obese status with genotypes (assuming an additive model), respectively. Results: During 6 years of follow-up, 158 previously obese children remained obese as they aged into adolescence, and 88 transiently obese children were not obese during the second survey, 58 children were newly identified obese, and the other 473 children remained their non-obese state. BMI Z-score increased from 1.41±0.05 at baseline to 1.57±0.06 at follow up.The genotypes of the SNPs except rs6499640(P=0.033) and rs6265(P=0.041) were in Hardy-Weinberg equilibrium in each group (P>0.05). Each additional copy of the rs9939609 A allele was significantly associated with an increase in BMI Z-score (β=0.205, P=0.014) during follow up. Per C allele of rs17782313 was associated with an increase in BMI Z-score at baseline (β=0.268, P=0.003). As the non-obese reference, a significantly relative risk of obesity at follow up was observed for children carrying rs9939609 A-allele versus the T-allele carriers (OR=2.37, 95%CI: 1.45-3.88, P=0.001). Rs17782313 C-allele was significantly increase the risk of obesity only at baseline (OR=1.79, 95%CI: 1.24-2.60, P=0.002). Rs1805081 A-allele was significantly associated with durative of obesity (OR=1.45, 95%CI: 1.04-2.03, P=0.028). Each unit higher genetic risk score was associated with increases risk of 0.18 times (OR=1.18, 95%CI: 1.05-1.33) in childhood transient obesity, and 0.22 times (OR=1.22, 95% CI: 1.06-1.42) in incident obesity at follow-up. But it was not significantly associated with persisted obesity during 6 years of follow-up (OR=1.09, 95% CI: 0.99-1.20). Conclusion: We confirmed that the change of BMI and obesity status in children was affected by different genetic factors. Individual who carries more risk alleles in obesity-related genes may increase the susceptibility to obesity.
目的： 前瞻性验证12个肥胖相关基因多态性与儿童BMI和肥胖状态变化的关联。 方法： 基于2004年4—10月开展的北京儿童青少年代谢综合征研究，2010年12月对其中1 624名基线年龄为6~11岁且具有BMI和基因位点数据的儿童进行随访，成功随访到777名儿童（基线肥胖者246名，非肥胖者531名）。将BMI转化为Z评分（BMIZ），并计算随访期间的变化量。采用国际肥胖问题工作组推荐的儿童青少年超重、肥胖筛查BMI值分类标准诊断肥胖。使用实时荧光定量PCR对12个位点单核苷酸多态性（SNP）（rs9939609，rs6499640，rs7138803，rs1805081，rs17782313，rs6265，rs10938397，rs6235，rs29941，rs2844479，rs10913469和rs4788102）进行分型检测，并用简单相加法计算个体的肥胖遗传风险评分（GRS）。分别以多元线性回归和多因素logistic回归模型分析SNP对儿童BMIZ变化量及肥胖的影响。 结果： 经过6年随访，持续性肥胖158例，一过性肥胖88例；新发肥胖58例，持续非肥胖473名。基线和随访时BMIZ分别为1.41±0.05和1.57±0.06。除rs6499640(P=0.033)和rs6265(P=0.041)位点外，其余10个位点SNP均符合哈迪-温伯格平衡（P>0.05）。rs9939609位点与随访期间BMIZ变化量的关联有统计学意义（β=0.205，P=0.014），即每增加1个A等位基因可引起随访期间BMIZ增加0.205；rs17782313与基线BMIZ水平的关联有统计学意义（β=0.268，P=0.003），即每增加1个C等位基因可引起基线BMIZ增加0.268个单位。rs9939609位点A等位基因增加肥胖风险（OR=2.37，95%CI：1.45~3.88）；rs17782313位点C等位基因增加儿童期一过性肥胖风险（OR=1.79，95%CI：1.24~2.60）；rs1805081位点A等位基因增加持续性肥胖风险（OR=1.45，95%CI：1.04~2.03）。GRS每增加1个风险等位基因，儿童一过性肥胖风险增加0.18倍（OR=1.18，95%CI：1.05~1.33），随访6年肥胖新发风险增加0.22倍（OR=1.22，95%CI：1.06~1.42），但随访期间持续性肥胖风险增加无统计学意义（OR=1.09，95%CI：0.99~1.20）。 结论： 儿童BMI和肥胖状态的变化受不同遗传因素的影响。多个肥胖相关基因的综合效应对肥胖罹患风险的影响不可忽视。.
Keywords: Body mass index; Childhood; Follow up; Obesity; Polymorphism, single nucleotide.