Department of Biomedical Informatics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Pediatr Diabetes. 2023;2023. doi: 10.1155/2023/5367637. Epub 2023 Sep 11.
Given the differential risk of type 1 diabetes (T1D) in offspring of affected fathers versus affected mothers and our observation that T1D cases have differential DNA methylation near the imprinted gene compared to controls, we examined whether methylation near mediates the association between T1D family history and T1D risk. In a nested case-control study of 87 T1D cases and 87 controls from the Diabetes Autoimmunity Study in the Young, we conducted causal mediation analyses at 12 region CpGs to decompose the effect of family history on T1D risk into indirect and direct effects. These effects were estimated from two regression models adjusted for the human leukocyte antigen DR3/4 genotype: a linear regression of family history on methylation (mediator model) and a logistic regression of family history and methylation on T1D (outcome model). For 8 of the 12 CpGs, we identified a significant interaction between T1D family history and methylation on T1D risk. Accounting for this interaction, we found that the increased risk of T1D for children with affected mothers compared to those with no family history was mediated through differences in methylation at two CpGs (cg27351978, cg00565786) in the region, as demonstrated by a significant pure natural indirect effect (odds ratio (OR) = 1.98, 95% confidence interval (CI): 1.06-3.71) and nonsignificant total natural direct effect (OR = 1.65, 95% CI: 0.16-16.62) (for cg00565786). In contrast, the increased risk of T1D for children with an affected father or sibling was not explained by DNA methylation changes at these CpGs. Results were similar for cg27351978 and robust in sensitivity analyses. Lastly, we found that DNA methylation in the region was associated (<0:05) with gene expression of nearby protein-coding genes , , , and . Results indicate that the maternal protective effect conferred through exposure to T1D may operate through changes to DNA methylation that have functional downstream consequences.
鉴于受影响父亲的子女患 1 型糖尿病 (T1D) 的风险与受影响母亲的子女不同，并且我们观察到 T1D 病例在印记基因附近的 DNA 甲基化程度与对照相比存在差异，我们研究了 T1D 家族史与 T1D 风险之间的关联是否由附近的甲基化介导。在来自青年糖尿病自身免疫研究的 87 例 T1D 病例和 87 例对照的嵌套病例对照研究中，我们对 12 个区域 CpG 进行了因果中介分析，以将家族史对 T1D 风险的影响分解为间接和直接影响。这些影响是通过两种调整人类白细胞抗原 DR3/4 基因型的回归模型估计的：家族史与甲基化的线性回归（中介模型）和家族史和甲基化与 T1D 的逻辑回归（结果模型）。对于 12 个 CpG 中的 8 个，我们发现 T1D 家族史与 T1D 风险之间存在显著的相互作用。考虑到这种相互作用，我们发现与没有家族史的儿童相比，受影响母亲的儿童患 T1D 的风险增加是由区域内两个 CpG（cg27351978，cg00565786）的甲基化差异介导的，这一点由显著的纯自然间接效应（比值比（OR）=1.98，95%置信区间（CI）：1.06-3.71）和非显著的总自然直接效应（OR=1.65，95%CI：0.16-16.62）（对于 cg00565786）表明。相比之下，受影响父亲或兄弟姐妹的儿童患 T1D 的风险增加不能用这些 CpG 处的 DNA 甲基化变化来解释。在敏感性分析中，cg27351978 的结果相似且稳健。最后，我们发现区域内的 DNA 甲基化与附近蛋白编码基因、、、和的基因表达相关（<0:05）。结果表明，通过接触 T1D 赋予的母体保护作用可能通过改变具有下游功能后果的 DNA 甲基化来发挥作用。
