中国女性出生体重与2型糖尿病风险的代际关联模式及生物学机制探讨

【Background】Malnutrition in early life has been an important risk factor for subsequent type 2 diabetes. Its effect on the risk of type 2 diabetes in offspring and possible mechanisms, however, remain unclear.【Objectives】To establish an trans-generational association model of birth weight with the risk of type 2 diabetes in Chinese females, and seek the possible epigenetic mechanisms underlying the associations.【Methods】Following-up surveys for an established family cohort which includes 10,324 females in communities of Shanghai, China, will be conducted to collect information on incident type 2 diabetes and blood samples to measure the levels of glycosylated homoglobin A1c (HbA1c), fasting insulin, and fasting and 2-hour postprandial blood glucose. Based on the female family cohort, we will select all 381 three-generation families with the first generation (F1) exposured to the Chinese famine to further assay methylation of loci implicated in the transcriptional regulation of 6 candidate genes for metabolic disease.The loci studied will include three imprinted loci of guanine nucleotide binding protein (GNASAS), insulin-like growth factor 2 (IGF-2), and insulin-like growth factor 2 receptor (IGF2R) and three non-imprinted loci of interleukin 10 (IL10), fat mass and obesity associated (FTO) and leptin (LEP). Cox model will be applied to evaluate the associations of birth weight with risk of type 2 diabetes in different birth cohorts. Path analysis and mediation analysis will be used to evaluate the impact of birth weight and type 2 diabetes of F1 generation on F2 and F3 generations.【Expected Results】In the view of phenotype and epigenetics, we will evaluate the trans-generational impact of birth weight on the risk of type 2 diabetes in Chinese females.【Significance】Our results will help to better understand the biological mechanisms underlying the increasing trend of T2DM in China, and aid to develop an effective intervention approach to curb the upward trend in the country.

【背景】女性生命早期营养不良是其成年后2型糖尿病（T2DM）发病的重要危险因素，但对其后代T2DM发病的关联性及其机理尚不清楚。【目的】研究我国女性出生体重（BW）与T2DM的代际关联模式，评估其关联强度，并探索相关机理。【方法】通过女性家庭大样本队列随访，评估BW与成年后空腹血糖、餐后血糖、糖化血红蛋白（HbA1c）、胰岛素水平以及T2DM发病风险的关联性；借助结构方程等统计模型，研究母亲代BW对女儿代和外孙女代BW及T2DM风险的影响；检测母亲代生命早期暴露于60年代饥荒的三代女性家庭的父源和母源印记基因及非印记基因的外周血甲基化水平，评估三代女性DNA甲基化的关联性，以及DNA甲基化与T2DM发病之间的关联。【预期结果】揭示BW与T2DM关联的代际传递模式以及DNA甲基化在T2DM跨代传递中的作用。【研究意义】揭示我国T2DM持续上升的原因，为新的干预措施提供依据。

背景.生命早期营养不良是成年期2型糖尿病（T2DM）等疾病的危险因素，但对后代疾病发生的影响及机理尚不清楚。.主要研究内容.以上海闵行11882名家庭队列女性成员为对象，评估女性出生体重（BW）与成年期T2DM、肥胖和高血压风险的关联及代际关联，探讨DNA甲基化在关联中可能的中介效应。.重要结果.女性BW与成年期血压及高血压风险无显著代际关联。低BW女性成年期T2DM风险增加，成年期T2DM风险随BW增加而降低。母女间BW及成年期T2DM具有代际关联，但母亲BW对女儿成年期T2DM风险无直接/间接作用。LEP CpG16 DNA甲基化与BW及T2DM发病均有关，但不是BW与T2DM的中介变量。IGF2-R CpG 8甲基化可以解释BW与WC关联的3.3%，但这种中介效应在家庭层面上未达显著水平。.关键数据.母女两代BW（r=0.34，p<0.0001）及DNA甲基化水平(r: 0.070～0.228)显著相关。母女两代的血压及高血压患病状况显著相关，但未见母亲BW对女儿血压的影响。女性T2DM风险随BW增加而下降，但达3500 g 后风险不再下降。与母亲没有T2DM的女性相比，母亲患T2DM的女性成年期T2DM风险增加（OR=2.02, 95%CI: 1.57, 2.60）。LEP CpG16甲基化水平与T2DM呈正相关（β=0.006, 95% CI: 0.0004, 0.0121），但并非BW与T2DM关联的中介因素。BW与成年期BMI呈正相关（β=0.505，p<0.0001），但与WHtR呈负相关（β=0.004，p=0.0004）。女儿BW可介导母亲BW与女儿成年期BMI（β: 0.106，95%CI: 0.042，0.175）及WHtR（β: -0.002，95%CI: -0.003，-0.001）的关联。在个体层面，BW通过IGF2-R CpG 8甲基化对WC的间接效应为0.04 (95%CI：0.02~0.06），IGF2-R CpG 8甲基化可解释两者关联的3.3%，但这种中介效应在家庭层面未达显著水平。.科学意义.研究结果揭示了我国肥胖及T2DM持续上升的原因及可能机制，为新的干预措施提供依据。