snoRNAs signature for detection of cardiac rejection after heart transplantation

Background/Introduction Small nucleolar RNAs (snoRNAs) are small non-coding RNAs, mainly located in the nucleolus of the cell. They have been known for decades for their role in ribosomal biogenesis and modification, but the contribution of these molecules to human pathologies is a relatively new area, especially in cardiovascular diseases. In the field of heart transplantation, there is still the need to identify new biomarkers for the non-invasive detection of cardiac rejection which can replace endomyocardial biopsy. Therefore, snoRNAs could be candidates to explore as novel rejection biomarkers. Purpose This study aimed to analyse the expression of snoRNAs in plasma samples from patients undergoing heart transplantation and evaluate their potential as diagnostic biomarkers for non-invasive detection of mild (grade 1R) and moderate/severe (grade ≥2R) cellular rejection. Methods We included consecutive plasma samples from transplant recipients undergoing routine endomyocardial biopsies. Non-coding RNA sequencing analysis (NovaSeq 6000 Sequencing System (Illumina)) was performed on 361 samples, 181 diagnosed with acute cellular rejection (Grade 1R, n=140; and Grade ≥2R, n=41) and 180 samples without cardiac rejection. Results We detected 142 non-coding RNAs of snoRNA and scaRNA biotype, of which 7 were altered in patients with cardiac rejection Grade ≥2R. We found that the combination of URS00004640CB (SNORA75), URS000045555D (SNORA71B), URS0000599BEA (SNORA2B) and URS000018895F (sno-lncRNA5), showed an excellent diagnostic ability in moderate/severe rejection (AUC=1, p<0.01), and they were also able to detect mild rejection (AUC=0.786, p<0.05). Conclusion We propose a molecular signature composed of snoRNA as potential biomarkers to detect cardiac rejection in plasma, offering a novel insight into the differential involvement of these molecules in the rejection pathophysiology.