ALSPAC研究中儿童血糖稳态轨迹的遗传与环境因素
该研究基于ALSPAC队列8783名7-24岁参与者的数据，计算12种多基因风险评分（PRS），评估其对血糖性状的预测性能及基因-环境交互作用。结果显示PRS增强模型优于仅环境因素模型（如15岁时血糖异常AUC提高0.12至0.78），空腹血糖PRS可中等区分暂时性与持续性糖尿病前期（AUC=0.70），且高遗传风险结合屏幕时间增加或母亲年龄较轻增加胰岛素抵抗风险。
要点
- PRS增强模型对青少年血糖异常的预测优于环境因素模型。
- 空腹血糖PRS可中等程度区分暂时性与持续性糖尿病前期。
- 高遗传风险叠加屏幕时间多或母亲年龄轻增加胰岛素抵抗风险。
核心结论
- 基因与环境交互作用共同决定青少年血糖稳态，可改变因素可作为早期预防的干预靶点。
研究设计与样本
- 基于ALSPAC队列8783名7-24岁参与者的数据，计算12种针对2型糖尿病、空腹血糖、胰岛素和BMI的PRS。
- 使用空腹血糖和胰岛素（7、15、18、24岁）及HbA1c（9岁）评估血糖结局，采用多项式回归区分暂时性与持续性血糖异常。
- 进行单变量和多变量回归纳入环境因素（生活方式、饮食和母亲特征），用R2和AUC评估模型性能，并检验PRS五分位数与环境因素的交互作用。
主要发现
- 24岁时糖尿病前期患病率高达24%。
- PRS增强模型优于仅用环境因素的模型，例如15岁时血糖异常AUC提高0.12，达到0.78。
- 空腹血糖PRS区分暂时性与持续性糖尿病前期的AUC=0.70。
- 基因-环境分析显示高遗传风险合并屏幕时间增加或母亲年龄较轻增加胰岛素抵抗风险，体力活动和健康意识可减弱该风险。
- 通路分析提示生命早期胰岛素分泌是关键机制，胰岛素抵抗 later 出现。
临床怎么用
- 在儿童和青少年血糖异常风险评估中可考虑结合PRS与环境因素以提高预测性能。
- 对高遗传风险个体，关注屏幕时间、体力活动和健康意识等可改变因素以降低胰岛素抵抗风险。
以上解读依据论文摘要（全文未开放获取或许可不允许翻译转载）。
原文
AIMS/HYPOTHESIS: Dysglycaemia in youth results from complex interactions between genetic and environmental factors, yet their individual and combined contributions remain unclear. We aimed to: (1) evaluate the predictive performance of polygenic risk scores (PRSs) for glycaemic traits from childhood to early adulthood; (2) identify gene-environment interactions shaping glucose homeostasis trajectories; and (3) explore underlying mechanisms using pathway-specific PRSs. METHODS: Data from 8783 participants (aged 7-24 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used to compute 12 PRSs for type 2 diabetes, fasting glucose, insulin and BMI. Glycaemic outcomes, including insulin resistance, prediabetes (impaired fasting glucose) and type 2 diabetes, were assessed using fasting glucose and insulin (ages 7, 15, 18 and 24 years) and HbA1c (age 9 years). We evaluated whether PRSs could distinguish between transient (resolved by adulthood) and persistent glycaemic abnormalities using multinomial regression. We performed univariate and multivariate regressions, incorporating environmental factors (lifestyle, diet and maternal characteristics), and evaluated model performance using R2 and AUC. We tested interactions between PRS quintiles and environmental factors and explored pathophysiological mechanisms using pathway-specific PRSs. RESULTS: Prediabetes prevalence was up to 24% at age 24 years. PRS-enhanced models outperformed those using environmental factors alone (e.g. AUC for dysglycaemia at age 15 improved by 0.12, reaching 0.78). Fasting glucose PRS showed moderate ability to differentiate transient from persistent prediabetes (AUC=0.70). Gene-environment analyses revealed that high genetic risk combined with increased screen time or younger maternal age increased insulin resistance risk. Physical activity and health awareness attenuated this risk. Pathway analyses indicated insulin secretion as a key mechanism earlier in life, with insulin resistance emerging later. CONCLUSIONS/INTERPRETATION: Genes interact with environment to define glucose homeostasis in youth, highlighting modifiable factors as actionable targets for early prevention.
引用
- Gamache I, Fagbemi K, Harnois-Leblanc S, et al. Nature vs nurture of glucose homeostasis trajectories in children from the ALSPAC study. Diabetologia. 2026. PMID: 41986816. doi:10.1007/s00125-026-06722-5
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