Background: Moyamoya disease (MMD) is a rare cerebrovascular disorder of unknown cause. Epigenetic regulations such as methylation play key role in gene expression and cerebrovascular diseases, however, methylation changes in MMD has not been previously reported. To understand the methylation profile of MMD, we performed a genome-wide DNA methylation analysis of whole blood from MMD patients.
Method: Twenty-eight female adult patients and age-/sex- matched 10 healthy control volunteers (34.2 ± 1.3y) were included. All patients developed TIA or headache and were diagnosed as typical MMD (n=19 and 9), predominantly with Suzuki’s angiographical stage 3. DNA was extracted from frozen whole blood and processed with bisulfide conversion. Genome-wide DNA methylation profile was screened using Illumina 850K EPIC microarray. Blood DNA methylome and clinical characteristics were analyzed.
Results: Self-declared race was predominantly Asian or Caucasian (n=14 and 13 in MMD, n=6 and 3 in control). Eleven patients showed asymptomatic cerebral infarct. MMD susceptible variant (rs112735431) was confirmed only in 4 Asian MMD. We observed distinct blood DNA methylation profile between Asian and Caucasian. There was no significant correlation between the methylation profile and symptom, infarct lesion, nor MMD susceptible variant. Our data revealed 51% of differentially methylated CpG probes (DMPs) in Caucasian MMD (P<0.01), located at CpG island or shore (51% of all the 5782 DMPs), and 3742 genes were regulated by these island/shore locating DMPs. IPA disease and bio-function profiler indicated that these genes involved in the adhesion of T lymphocytes and monocytes, as well as transmigration of peripheral blood lymphocytes.
Conclusion: Our results indicate that significant methylation changes occur in the blood of MMD patients. In Caucasian MMD, circulating T lymphocytes and monocytes may have a role in disease development, since these cells are known to participate in thickened fibrocellular intima in MMD. Ongoing studies are identifying the correlation of DNA methylation in blood and gene expression in the vascular tissue. Blood DNA methylation changes may be related with the risk of Caucasian MMD.