Abstract Body: Background: Moyamoya disease (MMD) is a chronic cerebrovascular disorder that can affect both children and adults. It is characterized by chronic and progressive narrowing of the cerebral arteries and the formation of fragile collateral blood vessels. The narrowed arteries can lead to lead to stroke and neurological dysfunctions. Considering that MMD is mostly sporadic and gene-environment interactions play an important in various diseases, we sought to investigate epigenetic modifications in MMD, focusing specifically on changes in DNA methylation magnitude and variability.
Methods: We performed genome-wide DNA methylation using Illumina 850K Methylation EPIC BeadChip, in two racially distinct adult female cohorts: A Non-Asian cohort (13 MMD patients and 7 healthy controls) and an Asian cohort (14 MMD patients and 3 healthy controls). An additional external cohort with both sexes (females: 5 MMD patients and 5 healthy controls, males: 5 MMD patients and 5 healthy controls) was included for validation.
Results: Our findings revealed subtle changes in the magnitude of DNA methylation, but a strikingly low DNA methylation variability between MMD patients and healthy controls across both female MMD cohorts. In the Non-Asian cohort, only 6 probes showed increased variability, compared to 647 probes that showed decreased variability. Similarly, in the Asian cohort, the MMD group also displayed a reduced methylation variability across all 2845 probes. Further analysis showed that these differentially variable probes are associated with genes involved in key biological processes such as methylation and transcription, DNA repair, cytoskeletal remodeling, natural killer cell signaling, cellular growth, and migration.
Conclusions: These findings mark the first observation of low methylation variability in any disease, contrasting with the high variability observed in other disorders. This reduced methylation variability in MMD may impair patients’ adaptability to environmental changes, such as hemodynamic stress, thereby disrupting vascular homeostasis and contributing to MMD pathology. These findings offer new insights into the mechanisms of MMD and suggest potential avenues for treatment strategies.