非糖尿病人群中糖尿病相关甲基化位点（TXNIP cg19693031）与空腹血糖水平变异体（GLUT1 rs841853）之间的相互作用。
Interaction between a diabetes-related methylation site (TXNIP cg19693031) and variant (GLUT1 rs841853) on fasting blood glucose levels among non-diabetics.
机构信息
Institute of Medicine, Chung Shan Medical University, Taichung City, 40201, Taiwan.
School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan.
出版信息
J Transl Med. 2022 Feb 14;20(1):87. doi: 10.1186/s12967-022-03269-y.
BACKGROUND
Type 2 diabetes mellitus (T2DM) is caused by a combination of environmental, genetic, and epigenetic factors including, fasting blood glucose (FBG), genetic variant rs841853, and cg19693031 methylation. We evaluated the interaction between rs841853 and cg19693031 on the FBG levels of non-diabetic Taiwanese adults.
METHODS
We used Taiwan Biobank (TWB) data collected between 2008 and 2016. The TWB data source contains information on basic demographics, personal lifestyles, medical history, methylation, and genotype. The study participants included 1300 people with DNA methylation data. The association of cg19693031 methylation (stratified into quartiles) with rs841853 and FBG was determined using multiple linear regression analysis. The beta-coefficients (β) and p-values were estimated.
RESULTS
The mean ± standard deviation (SD) of FBG in rs841853-CC individuals (92.07 ± 7.78) did not differ significantly from that in the CA + AA individuals (91.62 ± 7.14). However, the cg19693031 methylation levels were significantly different in the two groups (0.7716 ± 0.05 in CC individuals and 0.7631 ± 0.05 in CA + AA individuals (p = 0.002). The cg19693031 methylation levels according to quartiles were β < 0.738592 (< Q1), 0.738592 ≤ 0.769992 (Q1-Q2), 0.769992 ≤ 0.800918 (Q2-Q3), and β ≥ 0.800918 (≥ Q3). FBG increased with decreasing cg19693031 methylation levels in a dose-response manner (p = 0.005). The β-coefficient was - 0.0236 (p = 0.965) for Q2-Q3, 1.0317 (p = 0.058) for Q1-Q2, and 1.3336 (p = 0.019 for < Q1 compared to the reference quartile (≥ Q3). The genetic variant rs841853 was not significantly associated with FBG. However, its interaction with cg19693031 methylation was significant (p-value = 0.036). Based on stratification by rs841853 genotypes, only the CC group retained the inverse and dose-response association between FBG and cg19693031 methylation. The β (p-value) was 0.8082 (0.255) for Q2-Q3, 1.6930 (0.022) for Q1-Q2, and 2.2190 (0.004) for < Q1 compared to the reference quartile (≥ Q3). The p was 0.002.
CONCLUSION
Summarily, methylation at cg19693031 was inversely associated with fasting blood glucose in a dose-dependent manner. The inverse association was more prominent in rs841853-CC individuals, suggesting that rs841853 could modulate the association between cg19693031 methylation and FBG. Our results suggest that genetic variants may be involved in epigenetic mechanisms associated with FBG, a hallmark of diabetes. Therefore, integrating genetic and epigenetic data may provide more insight into the early-onset of diabetes.
背景
2 型糖尿病（T2DM）是由环境、遗传和表观遗传因素共同引起的，包括空腹血糖（FBG）、遗传变异 rs841853 和 cg19693031 甲基化。我们评估了非糖尿病台湾成年人中 rs841853 与 cg19693031 之间在 FBG 水平上的相互作用。
方法
我们使用 2008 年至 2016 年期间收集的台湾生物库（TWB）数据。TWB 数据源包含基本人口统计学、个人生活方式、病史、甲基化和基因型信息。研究参与者包括 1300 名具有 DNA 甲基化数据的人。使用多元线性回归分析确定 cg19693031 甲基化（分为四分位数）与 rs841853 和 FBG 的关联。估计了β系数（β）和 p 值。
结果
rs841853-CC 个体的 FBG 平均值±标准偏差（SD）（92.07±7.78）与 CA+AA 个体的 FBG 平均值（91.62±7.14）没有显著差异。然而，两组之间的 cg19693031 甲基化水平有显著差异（CC 个体为 0.7716±0.05，CA+AA 个体为 0.7631±0.05（p=0.002）。根据四分位数的 cg19693031 甲基化水平为β<0.738592（<Q1），0.738592≤0.769992（Q1-Q2），0.769992≤0.800918（Q2-Q3），β≥0.800918（≥Q3）。FBG 随着 cg19693031 甲基化水平的降低呈剂量反应方式增加（p=0.005）。β系数为-0.0236（p=0.965），用于 Q2-Q3，1.0317（p=0.058），用于 Q1-Q2，1.3336（p=0.019），用于<Q1 与参考四分位数（≥Q3）相比。遗传变异 rs841853 与 FBG 无显著相关性。然而，它与 cg19693031 甲基化的相互作用具有显著意义（p 值=0.036）。根据 rs841853 基因型分层，只有 CC 组保留了 FBG 与 cg19693031 甲基化之间的反向和剂量反应关系。β（p 值）为 0.8082（0.255），用于 Q2-Q3，1.6930（0.022），用于 Q1-Q2，1.2190（0.004），用于<Q1 与参考四分位数（≥Q3）相比。p 值为 0.002。
结论
总之，cg19693031 处的甲基化与空腹血糖呈剂量依赖性的负相关。在 rs841853-CC 个体中，这种负相关更为明显，表明 rs841853 可以调节 cg19693031 甲基化与 FBG 之间的关联。我们的结果表明，遗传变异可能参与与 FBG 相关的表观遗传机制，FBG 是糖尿病的标志。因此，整合遗传和表观遗传数据可能会更深入地了解糖尿病的早期发病机制。
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