胎儿IGF通路相关基因甲基化模式建立与其生长关系的分子流行病学研究

Fetal origin hypothesis considers that chronic diseases originate from fetal exposures. Many studies have provided evidence that fetal growth, particularly birth weight, is associated with chronic diseases in adulthood. Epigenetic change such as methylation has been considered as one important mechanism underlying fetal origin hypothesis. Insulin like growth factor pathway plays an essential role in fetal growth and methylation patterns of IGF genes have been linked to human cancer. To explore the relationship between IGF pathway gene methylation patterns and fetal growth and to investigate factors that influence methylation patterns will provide critical evidence to our understanding of fetal origin hypothesis. No study, however, has systemically investigated one carbon nutrients, genetic variation in one carbon metabolic pathway genes, and maternal methylation patterns in relation to fetal IGF pathway gene methylation patterns. Our pilot study suggested that maternal serum levels of vitamin B12 and maternal IGF2 gene methylation pattern were associated with fetal IGF2 gene methylation pattern. Building upon an established birth cohort study in Taiyun, we will use large sample size to systemically examine methylation patterns of fetal IGF pathway genes in relation to birth weight, as well as impact of one carbon nutrients, genetic polymorphisms in one carbon metabolic pathway genes, and maternal methylation patterns of IGF pathway genes on fetal IGF pathway gene methylation patterns. This study will have important public health implications and will provide scientific evidence for development of early life intervention strategies to prevent chronic diseases.

胎源学说认为成人慢性疾病源于宫内暴露，目前许多研究提示胎儿生长与成人慢性疾病有关，宫内暴露影响表观遗传的调节（如基因甲基化）可能是其中的一种机制。胰岛素样生长因子（IGF）通路在胎儿生长发育过程中起着极其重要的作用，且其基因甲基化模式与成人肿瘤相关。探索IGF通路相关基因甲基化模式对胎儿生长发育影响，研究影响IGF通路相关基因甲基化模式的因素将为揭示疾病的胎源学说提供重要依据。但目前尚无这方面的系统研究。课题组前期工作提示，胎儿IGF2基因甲基化与母亲维生素B12血清水平有关，且与母亲该基因甲基化有关。本课题拟在已建立的太原出生队列基础上，采用大样本，系统研究IGF通路相关基因甲基化模式与胎儿生长关系，并从一碳营养素摄入、一碳代谢通路相关基因多态性及表观遗传的可遗传性全面探讨胎儿IGF通路相关基因甲基化模式建立的影响因素。本研究从表观遗传角度揭示疾病胎源假说，促进疾病早期干预计划

目的：探讨 IGF 通路、氧化应激通路、胰岛素受体信号通路三条候选通路相关基因甲基化模式与胎儿生长的关系，并从一碳营养素摄入、一碳代谢通路相关基因多态性及遗传因素全面探讨胎儿基因甲基化模式建立的影响因素。.方法：采用病例对照研究的方法，随机选取50低出生体重（出生体重<2500g），50正常出生体重（出生体重2500-4000g）及50高出生体重（出生体重≥4000g）母婴对。用850K甲基化芯片检测母亲和胎儿基因甲基化水平，TaqMan 探针法检测母亲一碳代谢通路相关基因多态性，半定量食物频数表估计一碳营养素的摄入水平，分析一碳营养素摄入情况、相关基因多态性及遗传因素在胎儿甲基化模式建立中的作用及其对新生儿出生体重的影响。.结果：孕期蛋氨酸膳食摄入量Q2（789.29~967.74）mg/d、Q3（967.74~1247.45）mg/d能降低低出生体重的发生风险（分别为OR=0.604，95%CI：0.403~0.906；OR=0.483，95%CI：0.277~0.840），半胱氨酸摄入量为Q2（685.63~812.22）mg/d能降低高出生体重的发生风险（OR=0.676，95%CI：0.463~0.988）。暂未发现一碳代谢通路相关基因多态性与出生体重有关。除胎儿氧化应激相关基因甲基化模式外，IGF通路、胰岛素受体信号通路相关基因中36个位点甲基化模式与低出生体重有关，尚未发现以上三条通路相关基因甲基化模式与高出生体重有关。母亲孕期摄入一碳营养素与多个位点甲基化模式有关。母血AKT2基因cg07815521位点（r=0.408，P<0.0001）、IGF2BP1基因cg00441918位点（r=0.446，P<0.0001）、IRS2基因cg12195446位点（r=0.545，P<0.0001）、IRS4基因cg01980778（r=0.448，P=0.003）、PIK3AP1基因cg24973907位点（r=0.402，P<0.0001）、PIK3AP1基因cg10698635位点（r=0.435，P<0.0001）的甲基化与脐血相对应基因位点的甲基化相关。.结论：母亲一碳营养素摄入情况及遗传因素会影响胎儿三条候选通路即IGF通路、氧化应激通路、胰岛素受体信号通路相关基因甲基化模式，这些通路基因甲基化水平与胎儿低出生体重发生有关。