DNA methylation and 28-year cardiovascular disease risk in type 1 diabetes: the Epidemiology of Diabetes Complications (EDC) cohort study.

IF 5.7 2区 医学 Q1 Medicine Clinical Epigenetics Pub Date : 2023-08-02 DOI:10.1186/s13148-023-01539-0
Rachel G Miller, Josyf C Mychaleckyj, Suna Onengut-Gumuscu, Eleanor Feingold, Trevor J Orchard, Tina Costacou
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Abstract

Background: 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.

Results: 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%.

Conclusions: 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.

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1 型糖尿病患者 DNA 甲基化与 28 年心血管疾病风险:糖尿病并发症流行病学 (EDC) 队列研究。
背景:DNA甲基化(DNAm)作为心血管疾病(CVD)早期标志物的潜力,以及这种关联如何因血糖暴露而异,在心血管疾病风险增加的1型糖尿病人群中尚未得到研究。因此,我们对儿童期发病的 1 型糖尿病患者的血液白细胞 DNAm(EPIC 阵列)和心血管疾病发病时间进行了长达 28 年的前瞻性全表观基因组关联研究:28年间,172名参与者(46.7%)发生了心血管疾病(首次心血管疾病死亡、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,在心血管疾病发生时间的 Cox 回归模型中,所检测的 683,597 个 CpGs 在假发现率 (FDR) ≤ 0.05 时均未达到显著性。结论:这些结果提供了新的证据,表明与钙通道活性和发育有关的基因位点上的DNAm可能是导致1型糖尿病患者长期心血管疾病风险的因素,而不是已知的风险因素,尤其是在血糖暴露程度较高的人群中,这值得进一步研究。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
期刊最新文献
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