Institute of Epidemiology II, Helmholtz Zentrum München, Ingolstädter Landstraβe 1, 85764, Neuherberg, Germany.
Mailman School of Public Health, Columbia University, 722 W 168th St, New York, NY, 10032, USA.
Clin Epigenetics. 2018 Dec 27;10(1):161. doi: 10.1186/s13148-018-0588-7.
Most research into myocardial infarctions (MIs) have focused on preventative efforts. For survivors, the occurrence of an MI represents a major clinical event that can have long-lasting consequences. There has been little to no research into the molecular changes that can occur as a result of an incident MI. Here, we use three cohorts to identify epigenetic changes that are indicative of an incident MI and their association with gene expression and metabolomics.
Using paired samples from the KORA cohort, we screened for DNA methylation loci (CpGs) whose change in methylation is potentially indicative of the occurrence of an incident MI between the baseline and follow-up exams. We used paired samples from the NAS cohort to identify 11 CpGs which were predictive in an independent cohort. After removing two CpGs associated with medication usage, we were left with an "epigenetic fingerprint" of MI composed of nine CpGs. We tested this fingerprint in the InCHIANTI cohort where it moderately discriminated incident MI occurrence (AUC = 0.61, P = 6.5 × 10). Returning to KORA, we associated the epigenetic fingerprint loci with cis-gene expression and integrated it into a gene expression-metabolomic network, which revealed links between the epigenetic fingerprint CpGs and branched chain amino acid (BCAA) metabolism.
There are significant changes in DNA methylation after an incident MI. Nine of these CpGs show consistent changes in multiple cohorts, significantly discriminate MI in independent cohorts, and were independent of medication usage. Integration with gene expression and metabolomics data indicates a link between MI-associated epigenetic changes and BCAA metabolism.
大多数心肌梗死 (MI) 的研究都集中在预防措施上。对于幸存者来说，MI 的发生是一个重大的临床事件，可能会产生长期的后果。对于 MI 事件后可能发生的分子变化，几乎没有研究。在这里，我们使用三个队列来确定指示 MI 事件发生的表观遗传变化及其与基因表达和代谢组学的关联。
我们使用 KORA 队列的配对样本，筛选出甲基化变化可能表明基线和随访检查之间发生 MI 的 DNA 甲基化位点 (CpG)。我们使用 NAS 队列的配对样本在独立队列中识别出 11 个有预测作用的 CpG。在去除与药物使用相关的两个 CpG 后，我们留下了一个由 9 个 CpG 组成的 MI“表观遗传指纹”。我们在 InCHIANTI 队列中测试了这个指纹，它可以适度区分 MI 的发生 (AUC = 0.61，P = 6.5 × 10)。回到 KORA，我们将表观遗传指纹位点与顺式基因表达相关联，并将其整合到一个基因表达-代谢组学网络中，该网络揭示了表观遗传指纹 CpG 与支链氨基酸 (BCAA) 代谢之间的联系。
MI 后 DNA 甲基化有明显变化。其中 9 个 CpG 在多个队列中表现出一致的变化，在独立队列中显著区分 MI，且与药物使用无关。与基因表达和代谢组学数据的整合表明，MI 相关的表观遗传变化与 BCAA 代谢之间存在联系。
