■1型糖尿病(T1D)之前是异质的临床前阶段,胰岛自身免疫(IA)。我们的目标是确定pre与IA后血清转换(SV)的DNAm变化在三种IA进展表型中有所不同,那些失去自身抗体(回复器)的人,临床T1D进展(进展),或维持自身抗体水平(维持者)。
■这项全表观基因组关联研究(EWAS)包括开发IA的年轻糖尿病自身免疫研究(DAISY)参与者的血液中纵向DNAm测量(Illumina450K和EPIC),在至少两次连续访问中出现一种或多种胰岛自身抗体。我们比较了回复者——血清回复者,在至少两次连续访视中,所有自身抗体均呈阴性,且未出现T1D(n=41);维持者-自身抗体持续检测呈阳性,但未出现T1D(n=60);进展者-出现临床T1D(n=42).在IA之前(SV访视前)和之后(SV访视后)测量DNAm数据。线性混合模型用于测试三组中DNAm的前SV变化与后SV变化的差异。线性混合模型也用于测试平均DNAm的组差异。细胞比例,年龄,和性别在所有模型中都进行了调整。所有参与者的中位随访时间为15.5年。(四分位数间距(IQR):10.8-18.7)。
■SV前就诊的中位年龄为2.2岁。(IQR:0.8-5.3)在进展中,与6.0年相比。(IQR:1.3-8.4)在变频器中,5.7年。(IQR:1.4-9.7)在维护者。回转机1.4年的访问时间中位数相似。(IQR:1-1.9),维护者1.3年。(IQR:1.0-2.0),和进步1.8年。(IQR:1.0-2.0)。DNAm的变化,前与后SV,在一个地点(CG16066195)和11个地区的不同群体。平均DNAm(SV前后的平均值)在22个地区有所不同。
■差异变化的DNAm区域位于与β细胞功能相关的基因组区域,免疫细胞分化,和免疫细胞功能。
UNASSIGNED: Type 1 diabetes (T1D) is preceded by a heterogenous pre-clinical phase, islet autoimmunity (IA). We aimed to identify pre vs. post-IA seroconversion (SV) changes in DNAm that differed across three IA progression phenotypes, those who lose autoantibodies (reverters), progress to clinical T1D (progressors), or maintain autoantibody levels (maintainers).
UNASSIGNED: This epigenome-wide association study (EWAS) included longitudinal DNAm measurements in blood (Illumina 450K and EPIC) from participants in Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, one or more islet autoantibodies on at least two consecutive visits. We compared reverters - individuals who sero-reverted, negative for all autoantibodies on at least two consecutive visits and did not develop T1D (n=41); maintainers - continued to test positive for autoantibodies but did not develop T1D (n=60); progressors - developed clinical T1D (n=42). DNAm data were measured before (pre-SV visit) and after IA (post-SV visit). Linear mixed models were used to test for differences in pre- vs post-SV changes in DNAm across the three groups. Linear mixed models were also used to test for group differences in average DNAm. Cell proportions, age, and sex were adjusted for in all models. Median follow-up across all participants was 15.5 yrs. (interquartile range (IQR): 10.8-18.7).
UNASSIGNED: The median age at the pre-SV visit was 2.2 yrs. (IQR: 0.8-5.3) in progressors, compared to 6.0 yrs. (IQR: 1.3-8.4) in reverters, and 5.7 yrs. (IQR: 1.4-9.7) in maintainers. Median time between the visits was similar in reverters 1.4 yrs. (IQR: 1-1.9), maintainers 1.3 yrs. (IQR: 1.0-2.0), and progressors 1.8 yrs. (IQR: 1.0-2.0). Changes in DNAm, pre- vs post-SV, differed across the groups at one site (cg16066195) and 11 regions. Average DNAm (mean of pre- and post-SV) differed across 22 regions.
UNASSIGNED: Differentially changing DNAm regions were located in genomic areas related to beta cell function, immune cell differentiation, and immune cell function.