Department of Epidemiology, University of Pittsburgh, 130 N. Bellefield Avenue, Suite 339, Pittsburgh, PA, 15213, USA.
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Clin Epigenetics. 2023 Aug 2;15(1):122. doi: 10.1186/s13148-023-01539-0.
The potential for DNA methylation (DNAm) as an early marker for cardiovascular disease (CVD) and how such an association might differ by glycemic exposure has not been examined in type 1 diabetes, a population at increased CVD risk. We thus performed a prospective epigenome-wide association study of blood leukocyte DNAm (EPIC array) and time to CVD incidence over 28 years in a childhood-onset (< 17 years) type 1 diabetes cohort, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study (n = 368 with DNA and no CVD at baseline), both overall and separately by glycemic exposure, as measured by HbA1c at baseline (split at the median: < 8.9% and ≥ 8.9%). We also assessed whether DNAm-CVD associations were independent of established cardiometabolic risk factors, including body mass index, estimated glucose disposal rate, cholesterol, triglycerides, blood pressure, pulse rate, albumin excretion rate, and estimated glomerular filtration rate.
CVD (first instance of CVD death, myocardial infarction, coronary revascularization, ischemic ECG, angina, or stroke) developed in 172 participants (46.7%) over 28 years. Overall, in Cox regression models for time to CVD, none of the 683,597 CpGs examined reached significance at a false discovery rate (FDR) ≤ 0.05. In participants with HbA1c < 8.9% (n = 180), again none reached FDR ≤ 0.05, but three were associated at the a priori nominal significance level FDR ≤ 0.10: cg07147033 in MIB2, cg12324048 (intergenic, chromosome 3), and cg15883830 (intergenic, chromosome 1). In participants with HbA1c ≥ 8.9% (n = 188), two CpGs in loci involved in calcium channel activity were significantly associated with CVD (FDR ≤ 0.05): cg21823999 in GPM6A and cg23621817 in CHRNA9; four additional CpGs were nominally associated (FDR ≤ 0.10). In participants with HbA1c ≥ 8.9%, DNAm-CVD associations were only modestly attenuated after cardiometabolic risk factor adjustment, while attenuation was greater in those with HbA1c < 8.9%. No pathways were enriched in those with HbA1c < 8.9%, while pathways for calcium channel activity and integral component of synaptic membrane were significantly enriched in those with HbA1c ≥ 8.9%.
These results provide novel evidence that DNAm at loci involved in calcium channel activity and development may contribute to long-term CVD risk beyond known risk factors in type 1 diabetes, particularly in individuals with greater glycemic exposure, warranting further study.
DNA 甲基化（DNAm）作为心血管疾病（CVD）的早期标志物的潜力，以及这种关联在 1 型糖尿病患者中是否因血糖暴露而有所不同，在该人群中 CVD 风险增加。因此，我们对童年发病（<17 岁）1 型糖尿病队列（Pittsburgh 糖尿病并发症流行病学研究（EDC）研究）中的血液白细胞 DNAm（EPIC 阵列）和 28 年 CVD 发病时间进行了前瞻性全基因组关联研究，参与者共 368 名，基线时无 CVD 和 DNAm。总体而言，根据基线时 HbA1c（分为中位数以下：<8.9%和≥8.9%），我们分别按血糖暴露进行了评估。我们还评估了 DNAm-CVD 关联是否独立于已建立的心血管代谢危险因素，包括体重指数、估计葡萄糖处置率、胆固醇、甘油三酯、血压、脉搏率、白蛋白排泄率和估计肾小球滤过率。
在 28 年内，172 名参与者（46.7%）发生了 CVD（首次 CVD 死亡、心肌梗死、冠状动脉血运重建、缺血性心电图、心绞痛或中风）。总体而言，在 CVD 时间的 Cox 回归模型中，在 FDR≤0.05 时，没有一个 683597 个 CpG 达到显著水平。在 HbA1c<8.9%的参与者中（n=180），同样没有一个达到 FDR≤0.05，但有三个达到了先验名义显著性水平 FDR≤0.10：cg07147033 在 MIB2 中，cg12324048（位于 3 号染色体的基因间）和 cg15883830（位于 1 号染色体的基因间）。在 HbA1c≥8.9%的参与者中（n=188），两个参与钙通道活性的基因座中的 CpG 与 CVD 显著相关（FDR≤0.05）：cg21823999 在 GPM6A 中，cg23621817 在 CHRNA9 中；另外四个 CpG 达到了名义相关（FDR≤0.10）。在 HbA1c≥8.9%的参与者中，DNAm-CVD 关联在调整心血管代谢危险因素后仅略有减弱，而在 HbA1c<8.9%的参与者中，减弱幅度更大。在 HbA1c<8.9%的参与者中没有富集途径，而钙通道活性和突触膜完整成分的途径在 HbA1c≥8.9%的参与者中显著富集。
这些结果提供了新的证据，表明钙通道活性和发育相关基因座的 DNAm 可能有助于 1 型糖尿病患者的长期 CVD 风险，超过了已知的危险因素，特别是在血糖暴露较高的个体中，值得进一步研究。
