宫内营养过剩、肥胖相关基因甲基化与儿童肥胖关联性的队列研究

Childhood obesity becomes one of the significant health issues which poses significant impact on the quality of the populations and economic development in China. The fetuses that are exposed to adverse intrauterine environment may have already been ‘programmed’ to becoming obese in their later life. ‘Intrauterine overnutrition statuses’ associated with pre-pregnancy obesity, gestational weight gain and gestational diabetes mellitus during pregnancy are likely to alter the methylation status of obesity-related genes, hence to lead to obesity in childhood. However, there is a lack of population study evidences on this likelihood. This study, based on the already established mother-infant cohort in Zhuhai city, aims to follow up 200 mother-infant dyads, with 100 as exposure (intrauterine overnutrition) and 100 as control (normal intrauterine nutrition). The growth variables and early life patterns in children are to be dynamically measured and collected with their growth and obesity statuses assessed with the references to the well-recognised growth standards. An overall holistic strategy is to be implemented in the selection of the candidate obesity-related genes, and the methylation status of these selected genes, derived from umbilical cord blood samples, is to be analyzed using MethyLight PCR. Bio-statistical and bioinformatic analyses are to be employed to detect the associations of growth and obesity in children with intrauterine overnutrition status and the methylation of obesity-related genes. Important findings from this study will be verified in the Wuhan mother-infant cohort. It is expected that the results of the study provide firmer scientific grounds for screening out high-risk populations of obesity in the early years of life and for formulating the strategy of early prevention, and as well attach significant theoretical and practical importance.

儿童肥胖是影响我国人口质量和经济发展的重大公共卫生问题。胚胎期不良环境暴露可能已经“编程”未来的肥胖问题。孕前肥胖、孕期体重增长过多和妊娠期糖尿病造成“宫内营养过剩”的不利环境，极有可能通过影响肥胖相关基因甲基化而导致儿童肥胖，但人群证据缺乏。本研究利用已建成的珠海母婴队列，随访100对暴露组（宫内营养过剩）孕妇及儿童和100对孕期营养正常的孕妇及儿童，动态采集儿童体格发育和早期生活方式数据，参照公认儿童生长标准判断发育水平和肥胖状态；采用综合策略选定候选肥胖相关基因，采用TaqMan荧光定量PCR分析脐血候选基因甲基化状态；运用生物统计学和生物信息学方法，分析宫内营养过剩、肥胖相关基因甲基化与儿童体格发育水平和肥胖的关联。重要发现将在湖北队列（武汉人群）中予以验证。研究结果可为早期甄别肥胖高危人群和制定预防策略提供科学依据，具有重要的理论和现实意义。

背景：儿童超重肥胖已成为重要的公共卫生问题，其发生发展受到遗传和环境因素的综合影响。生命早期1,000天内(即从受孕到出生后两岁)的营养状况可能影响个体代谢“编程”，进而对后期的体重状态产生重要影响。.本研究重点探讨了以下三个方面的内容：.1. 孕前体重状态、孕期血压状态与婴儿期 12 月龄体重状态的关联.2. 孕前超重肥胖、母乳喂养持续时间与学龄前儿童超重肥胖的关联.3. 学龄前儿童超重肥胖的脐血DNA甲基化机制研究进行了探讨.主要结果：.1. 与孕前正常体重+孕期正常血压组比较，孕前超重肥胖+妊娠期高血压综合征组子代12月龄BMI-z评分水平高0.62个单位。孕前超 重肥胖和妊娠期高血压综合征的联合作用可增加子代12月龄婴儿高体重状态的风险(OR 3.10，95% CI 1.59，6.04)，其中51%(AP 0.51，95% CI 0.13，0.89)风险归因于相加交互作用。.2. 学龄前儿童(3岁)超重肥胖率为 12.2%(男生14.5%，女生9.7%)。孕前超重肥胖可显著增加学龄前儿童超重肥胖的风险(OR 2.36，95% CI 1.41，3.94)。限制性立方样条结果显示，母乳喂养持续时间与学龄前儿童超重肥胖存在非线性剂量-反应关系(P<0.001)。在母乳喂养持续时间≥6 个月的组中，未见孕前超重肥胖与学龄前儿童超重肥胖的统计学关联(OR 1.70，95% CI 0.79，3.63)。.3. 30对母亲血与脐血的全基因组DNA甲基化关联研究中，经FDR校正后，P值较小的位点(接近1×10-6)提示可能与孕前BMI或3岁BMI-z评分相关。性别、年龄别匹配的学龄前儿童超重肥胖与体重正常组(4:12)的脐血全基因组DNA甲基化关联研究结果发现59个脐血差异甲基化区域和371个差异位点。脐血差异甲基化区域主要富集于代谢通路、脂肪细胞因子通路、胰高血糖素信号通。.结论：孕前超重肥胖可能是早期儿童超重肥胖的危险因素。脐血FOXN3和AHRR基因甲基化可能与儿童早期超重肥胖相关，脐血FOXN3以及ZNF264基因甲基化可能与儿童早期BMI-z评分相关，且脐血FOXN3基因甲基化与孕前BMI相关，提示其可能介导孕前 BMI与儿童早期BMI-z评分或超重肥胖的关联。保证6个月的母乳喂养对于降低儿童早期超重肥胖风险，以及部分抵消孕前超重肥胖对子代体重的不良影响至关重要。