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bioRxiv · 10.1101/2021.03.10.434822

Identification of Cell-Free DNA Methylation Patterns Unique to the Human Left Ventricle as a Potential Indicator of Acute Cellular Rejection

Pattar, S.·Aleinati, M.·Iqbal, F.·Made, A.·Blais, S.·Wang, X.·Dallaire, F.·Wang, Y.·Isaac, D.·Fine, N.·Greenway, S. C.
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Abstract

Increased levels of donor-derived cell-free DNA (dd-cfDNA) in recipient plasma have been associated with rejection after transplantation. DNA sequence differences have been used to distinguish between donor and recipient but epigenetic differences could also potentially identify dd-cfDNA. This pilot study aimed to identify ventricle-specific differentially methylated regions of DNA (DMRs) that could be detected in cfDNA. We identified 24 ventricle-specific DMRs and chose two for further study, one on chromosome 9 and one on chromosome 12. The specificity of both DMRs for the left ventricle was confirmed using genomic DNA from multiple human tissues. Serial matched samples of myocardium (n=33) and plasma (n=24) were collected from stable adult heart transplant recipients undergoing routine endomyocardial biopsy for rejection surveillance. Plasma DMR levels increased with biopsy-proven rejection grade for individual patients. Mean cellular apoptosis in biopsy samples increased significantly with rejection severity (2.4%, 4.4% and 10.0% for ACR 0R, 1R and 2R, respectively) but did not show a consistent relationship with DMR levels. We identified multiple DNA methylation patterns unique to the human ventricle and conclude that epigenetic differences in cfDNA populations represent a promising alternative strategy for the non-invasive detection of rejection.

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Pattar, S., Aleinati, M., Iqbal, F., Made, A., Blais, S., Wang, X., Dallaire, F., Wang, Y., Isaac, D., Fine, N., Greenway, S. C.. 2021-03-10. Identification of Cell-Free DNA Methylation Patterns Unique to the Human Left Ventricle as a Potential Indicator of Acute Cellular Rejection. https://doi.org/10.1101/2021.03.10.434822

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