Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Population Sciences Branch, National Heart, Lung and Blood Institutes of Health, Bethesda, MD, USA.
Clin Epigenetics. 2023 Oct 27;15(1):173. doi: 10.1186/s13148-023-01589-4.
Insulin resistance (IR) is a major risk factor for Alzheimer's disease (AD) dementia. The mechanisms by which IR predisposes to AD are not well-understood. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus improving our understanding of the biological and regulatory mechanisms linking IR and AD.
We conducted an epigenome-wide association study of IR, quantified using the homeostatic model assessment of IR (HOMA-IR) and adjusted for body mass index, in 3,167 participants from the Framingham Heart Study (FHS) without type 2 diabetes at the time of blood draw used for methylation measurement. We identified DNA methylation markers associated with IR at the genome-wide level accounting for multiple testing (P < 1.1 × 10) and evaluated their association with neurological traits in participants from the FHS (N = 3040) and the Religious Orders Study/Memory and Aging Project (ROSMAP, N = 707). DNA methylation profiles were measured in blood (FHS) or dorsolateral prefrontal cortex (ROSMAP) using the Illumina HumanMethylation450 BeadChip. Linear regressions (ROSMAP) or mixed-effects models accounting for familial relatedness (FHS) adjusted for age, sex, cohort, self-reported race, batch, and cell type proportions were used to assess associations between DNA methylation and neurological traits accounting for multiple testing.
We confirmed the strong association of blood DNA methylation with IR at three loci (cg17901584-DHCR24, cg17058475-CPT1A, cg00574958-CPT1A, and cg06500161-ABCG1). In FHS, higher levels of blood DNA methylation at cg00574958 and cg17058475 were both associated with lower IR (P = 2.4 × 10 and P = 9.0 × 10), larger total brain volumes (P = 0.03 and P = 9.7 × 10), and smaller log lateral ventricular volumes (P = 0.07 and P = 0.03). In ROSMAP, higher levels of brain DNA methylation at the same two CPT1A markers were associated with greater risk of cognitive impairment (P = 0.005 and P = 0.02) and higher AD-related indices (CERAD score: P = 5 × 10 and 0.001; Braak stage: P = 0.004 and P = 0.01).
Our results suggest potentially distinct epigenetic regulatory mechanisms between peripheral blood and dorsolateral prefrontal cortex tissues underlying IR and AD at CPT1A locus.
胰岛素抵抗（IR）是阿尔茨海默病（AD）痴呆的主要危险因素。IR 导致 AD 的机制尚不清楚。表观遗传学研究可能有助于确定与 AD 相关的 IR 分子特征，从而提高我们对 IR 和 AD 之间生物学和调节机制的理解。
我们对来自弗雷明汉心脏研究（FHS）的 3167 名参与者进行了胰岛素抵抗的全基因组关联研究，使用稳态模型评估胰岛素抵抗（HOMA-IR）进行量化，并根据体重指数进行了调整，这些参与者在进行甲基化测量时没有 2 型糖尿病。我们在全基因组水平上确定了与胰岛素抵抗相关的 DNA 甲基化标记物，这些标记物考虑了多重检验（P<1.1×10），并评估了它们与 FHS 参与者（N=3040）和宗教秩序研究/记忆和衰老项目（ROSMAP，N=707）的神经特征之间的关联。使用 Illumina HumanMethylation450 BeadChip 在血液（FHS）或背外侧前额叶皮层（ROSMAP）中测量 DNA 甲基化谱。使用线性回归（ROSMAP）或混合效应模型（考虑家族相关性，FHS），根据年龄、性别、队列、自我报告的种族、批次和细胞类型比例进行调整，以评估 DNA 甲基化与神经特征之间的关联，这些关联考虑了多重检验。
我们在三个基因座（cg17901584-DHCR24、cg17058475-CPT1A、cg00574958-CPT1A 和 cg06500161-ABCG1）确认了血液 DNA 甲基化与胰岛素抵抗之间的强烈关联。在 FHS 中，cg00574958 和 cg17058475 处的血液 DNA 甲基化水平升高均与胰岛素抵抗降低（P=2.4×10 和 P=9.0×10）、总脑体积增大（P=0.03 和 P=9.7×10）和侧脑室体积log 减小（P=0.07 和 P=0.03）相关。在 ROSMAP 中，相同两个 CPT1A 标记物的大脑 DNA 甲基化水平升高与认知障碍风险增加（P=0.005 和 P=0.02）和 AD 相关指数升高相关（CERAD 评分：P=5×10 和 0.001；Braak 分期：P=0.004 和 P=0.01）。
我们的结果表明，在 CPT1A 基因座，IR 和 AD 之间的外周血和背外侧前额叶皮层组织中可能存在潜在的不同表观遗传调控机制。
