生命早期营养不良与成年期心血管病风险的回顾性队列及其表观遗传机制

The situation of cardiovascular diseases remains very serious in China nowadays. There are more than 2.9 billion patients, and 41% of death from was caused by cardiovascular diseases. Because of ethical and practical reasons, a large number of epidemiological studies focus on the associations between low birth weight and cardiovascular diseases. However, the direct evidence of malnutrition in early life and cardiovascular diseases in adulthood was less or insufficient, especially those studied the interactions of malnutrition in preschool children and match-mismatch acquired environment (including dietary nutrition environment and life style). This retrospective cohort selected 800 participants born from Oct 1954 to Sep 1964, and the level of malnutrition was determined by the proportion of food reduction in the two provinces from 1959 to 1961. The subjects were divided into four groups: non-exposed cohort, fetal-exposed cohort, infant-exposed cohort and preschool exposed cohort. We investigated the regional difference of prevalence of coronary heart disease, stroke and hypertension; analyzed the associations and interactions between malnutrition in early life and match-mismatch acquired environment on the risk of cardiovascular diseases; studied the associations between the DNA methylation of IGF-2、INS和GNA-AS and the formation of cardiovascular diseases. The present study may give direct evidence for the developmental origins of health and disease and also the early prevention of adulthood diseases.

目前我国心血管病形势仍十分严峻，患病人数达2.9亿，因心血管病死亡占总死因的41%。由于伦理的约束，大量流行病学研究只观察到低出生体重与心血管病的相关性，而关于生命早期营养不良与心血管病风险的直接证据较少，尤其是学龄前期营养缺乏与后天环境匹配/不匹配（包括膳食营养环境和生活方式）的交互作用更为少见。本项目选取1954年至1964年出生的约800人作为回顾性队列研究对象，根据选定省份1959年至1961年粮食减产的比例划分重度和轻度营养缺乏暴露，按出生日期分为未暴露、胎儿期、婴幼儿期和学龄前期暴露4个出生队列，比较不同时期暴露队列的冠心病、脑卒中和高血压患病率的地区差异，分析不同时期营养缺乏对成年期心血管病的影响及其与后天环境的交互作用，同时探讨IGF-2、INS和GNA-AS的DNA甲基化改变与心血管病形成的关系，从流行病学和分子生物学两方面为成年期慢性疾病的早期预防提供直接证据和策略。

本项目在安徽省（重度饥荒暴露）和江西省（轻度饥荒暴露）选取1954年至1964年出生的788人作为回顾性队列研究对象，按出生日期分为未暴露、胎儿期、婴幼儿期和学龄前期暴露4个出生队列，通过体格检查和调查问卷获得研究对象人口特征和既往疾病史，通过血清和DNA分析获得IGF2等基因甲基化水平，分析结果显示，婴儿期和胎儿期暴露可分别显著增加成年期发生高血压（OR=1.73; 95%CI: 1.26-2.37）和高总胆固醇血症（OR=1.63; 95%CI:1.19-2.24）风险，尤其是女性和重度饥荒暴露地区；学龄前期暴露显著增加成年期患冠心病（OR=2.79; 95%CI:1.07-7.28）和代谢综合征（OR=1.56; 95%CI:1.04-2.34）的风险，尤其是重度饥荒暴露地区。胎儿期（d=5.4; 95%CI: 2.6-8.2）和婴儿期（d=3.6; 95%CI: 0.9-6.3）暴露显著增加成年期外周血INSR基因的甲基化水平，而胎儿期饥荒暴露显著增加成年期外周血IGF2基因的甲基化水平（d=4.2; 95%CI: 1.4-7.03）。INSR基因启动子区的甲基化水平与高密度脂胆固醇脂蛋白和甘油三脂关联显著（Pearson相关系数分别为0.156和-0.179），而未发现IGF2、INSR、CPT1A基因甲基化水平与舒张压、收缩压、空腹血糖和腰围的关联。本研究进一步为健康与疾病的发育起源学说（DOHaD）提供了直接证据，提示了生命早期营养缺乏和人类健康结局的远期效应，有较好的现实意义。