Proteomics in acute heart transplant rejection, on behalf of the GRAfT Investigators.
Goldberg, J. F., de Filippi, C. R., Lockhart, C., McNair, E. R., Sinha, S., Kong, H., Najjar, S. S., Lohmar, B. J., Tchoukina, I., Shah, K., Feller, E., Hsu, S., Rodrigo, M. E., Jang, M., Marboe, C. C., Berry, G. J., Valantine, H. A., Agbor-Enoh, A., & Shah, P.
Publication Details
- Journal: Transplantation
- Date: December 2, 2024
- Status: in press
- DOI: 10.1097/TP.0000000000005258
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Abstract
Background: Proteomic phenotyping can provide insights into rejection pathophysiology, novel biomarkers, and therapeutic targets. Methods: Within the prospective, multicenter Genomic Research Alliance for Transplantation (GRAfT) study, 181 proteins were evaluated from blood drawn at time of endomyocardial biopsy; protein fold-change, logistic regression, and pathway analysis were analyzed, with protein discovery adjusted for a 5% false discovery rate. Results: Among 104 adult heart transplant patients (31% Female sex, 53% Black race, median age 52 years), 74 had no rejection, 18 developed acute cellular rejection (ACR), and 12 developed antibody-mediated rejection (AMR). Differential expression was found in 2 proteins during ACR (inflammatory proteins CXCL10 and CD5) and 73 proteins during AMR. The most abundant AMR proteins were the heart failure biomarkers N-terminal pro B-type natriuretic peptide (NT-proBNP) and suppression of tumorigenicity 2 (ST2). In univariate logistic regression, odds of identifying ACR on endomyocardial biopsy increased with doubling of CXCL10 (OR 2.2[95%CI: 1.3–3.6]) and CD5 (OR 4.7[95%CI: 1.7–12.9]) concentrations, and odds of AMR increased with doubling of NT-proBNP (OR 13.0[95%CI: 2.7–62.7) and ST2 (OR 4.8[95%CI: 2.1–10.7]) concentrations. After multivariable analysis with clinical covariates, these proteins showed similar odds of ACR or AMR outcomes. Pathway analysis identified T cell receptor signaling and differentiation in ACR, and cardiovascular disease and cell turnover in AMR. Conclusions: Proteomic analysis reveals unique biomarker and pathway expression in ACR and AMR. Cardiac injury-associated biomarkers were more pronounced in AMR, while inflammatory biomarkers were more pronounced in ACR. Proteomic analysis may provide insights into rejection pathophysiology, detection, and therapy.