Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
Diabetes Research Envision and Accomplished in Manitoba (DREAM) Theme of the Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.
Clin Epigenetics. 2024 May 13;16(1):65. doi: 10.1186/s13148-024-01675-1.
Youth-onset type 2 diabetes (T2D) is physiologically distinct from adult-onset, but it is not clear how the two diseases differ at a molecular level. In utero exposure to maternal type 2 diabetes (T2D) is known to be a specific risk factor for youth-onset T2D. DNA methylation (DNAm) changes associated with T2D but which differ between youth- and adult-onset might delineate the impacts of T2D development at different ages and could also determine the contribution of exposure to in utero diabetes.
We performed an epigenome-wide analysis of DNAm on whole blood from 218 youth with T2D and 77 normoglycemic controls from the iCARE (improving renal Complications in Adolescents with type 2 diabetes through REsearch) cohort. Associations were tested using multiple linear regression models while adjusting for maternal diabetes, sex, age, BMI, smoking status, second-hand smoking exposure, cell-type proportions and genetic ancestry.
We identified 3830 differentially methylated sites associated with youth T2D onset, of which 3794 were moderately (adjusted p-value < 0.05 and effect size estimate > 0.01) associated and 36 were strongly (adjusted p-value < 0.05 and effect size estimate > 0.05) associated. A total of 3725 of these sites were not previously reported in the EWAS Atlas as associated with T2D, adult obesity or youth obesity. Moreover, three CpGs associated with youth-onset T2D in the PFKFB3 gene were also associated with maternal T2D exposure (FDR < 0.05 and effect size > 0.01). This is the first study to link PFKFB3 and T2D in youth.
Our findings support that T2D in youth has different impacts on DNAm than adult-onset, and suggests that changes in DNAm could provide an important link between in utero exposure to maternal diabetes and the onset of T2D.
青年起病 2 型糖尿病（T2D）在生理学上有别于成人起病，但尚不清楚这两种疾病在分子水平上有何不同。已知母体 2 型糖尿病（T2D）暴露是青年起病 T2D 的特定危险因素。与 T2D 相关但在青年和成年发病之间存在差异的 DNA 甲基化（DNAm）变化可能阐明了不同年龄 T2D 发展的影响，也可能决定了胎儿期糖尿病暴露的贡献。
我们对来自 iCARE（通过研究改善青少年 2 型糖尿病的肾脏并发症）队列的 218 名青年 T2D 患者和 77 名血糖正常对照者的全血进行了 DNAm 的全基因组分析。使用多元线性回归模型进行关联检验，同时调整了母体糖尿病、性别、年龄、BMI、吸烟状态、二手烟暴露、细胞类型比例和遗传背景。
我们鉴定出与青年 T2D 发病相关的 3830 个差异甲基化位点，其中 3794 个位点（调整后的 p 值<0.05 和效应大小估计值>0.01）中度相关，36 个位点（调整后的 p 值<0.05 和效应大小估计值>0.05）高度相关。这些位点中有 3725 个以前未在 EWAS 图谱中被报道与 T2D、成人肥胖或青年肥胖相关。此外，与 PFKFB3 基因中与青年起病 T2D 相关的 3 个 CpG 也与母体 T2D 暴露相关（FDR<0.05 和效应大小>0.01）。这是第一项将 PFKFB3 与青年 T2D 联系起来的研究。
我们的研究结果支持青年 T2D 对 DNAm 的影响与成人发病不同，并表明 DNAm 的变化可能为母体糖尿病暴露与 T2D 发病之间提供重要联系。
