Proteomic Profiling of Heart Transplant Recipients Identifies CLE4C Expression as a Novel Biomarker of Primary Graft Dysfunction
The Journal of Heart and Lung Transplantation, 2021
Truby L., Kwee L., Agarwal R., Grass E., Devore A., Patel C., Rogers J., Chen D., Schroder J., Milano C., Shah S., Holley C.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Immunological & Inflammatory Diseases | Pathophysiology Patient Stratification | Serum |  Olink Target 96 |
Abstract
Purpose
Models to identify those at high risk of primary graft dysfunction (PGD) after heart transplantation (HT) are lacking and the pathophysiology remains poorly understood. We sought to identify whether proteins reporting on immune activation and inflammation were associated with incident PGD.
Methods
Using the Olink platform, we performed proteomic profiling of pre-transplant serum samples from HT recipients. PGD was defined using modified ISHLT criteria. We tested the association between PGD and protein levels using logistic regression with adjustment for clinical covariates (recipient age, creatinine, MCS, and sex; donor age; ischemic time). Significant proteins (p<0.05 in both unadjusted and clinical models) were identified in a derivation cohort and tested in a validation set. We used pathway enrichment analysis to test candidate biological processes, and compared the predictive performance of proteins to that of the RADIAL score.
Results
The derivation cohort consisted of 157 adult HT recipients, among whom 47 had PGD. Eleven of 368 proteins were associated with PGD in unadjusted and adjusted models and were tested in a validation cohort of 62 patients. The strongest association in the derivation cohort was with CLEC4C (OR [95%CI] = 2.0 [1.4,3.1], p=5.4 × 10−4), which remained the most significant tested protein in the validation set (OR [95%CI] = 1.8 [0.9,3.8], p=0.10; p<0.001 in joint analysis). Pathway analysis identified IFN-a (p=0.02) and TNF-a (p=0.01) signaling as significantly enriched biologic processes. The RADIAL score was a very poor predictor of PGD (AUC = 0.55). The addition of CLEC4C (AUC = 0.70, p=0.06) or all 11 proteins (AUC = 0.78, p=0.006) improved discrimination for PGD risk (Figure 1).
Conclusion
CLEC4C, a marker of plasmacytoid dendritic cells (PDC) which play a pro-inflammatory role via IFN-α signaling, may identify HT recipients at the highest risk for PGD. Further studies are needed to better understand the potential role of PDCs in PGD.