Racial Differences in Donor-Derived Cell-Free DNA and Mitochondrial DNA After Heart Transplantation, on Behalf of the GRAfT Investigators
Palak Shah, Sean Agbor-Enoh, Ben Seiyon Lee, T. Andargie, Shashank S. Sinha, Hyesik Kong, Lawrence Henry, Woojin Park, Erick McNair, Inna Tchoukina, Keyur B. Shah, Samer S. Najjar, Steven Hsu, M.E. Rodrigo, Moon Kyoo Jang, Charles C. Marboe, Gerald J. Berry, Hannah A. Valantine, on behalf of the GRAfT Investigators
Abstract
BACKGROUND: Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. We hypothesized that this risk may be associated with higher levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA. METHODS: The Genomic Research Alliance for Transplantation is a multicenter, prospective, longitudinal cohort study. Sequencing was used to quantitate dd-cfDNA and polymerase chain reaction to quantitate cell-free mitochondrial DNA in plasma. AR was defined as ≥2R cellular rejection or ≥1 antibody-mediated rejection. The primary composite outcome was AR, graft dysfunction (left ventricular ejection fraction <50% and decrease by ≥10%), or death. RESULTS: We included 148 patients (65 Black patients and 83 White patients), median age was 56 years and 30% female sex. The incidence of AR was higher in Black patients compared with White patients (43% versus 19%; P =0.002). Antibody-mediated rejection occurred predominantly in Black patients with a prevalence of 20% versus 2% ( P <0.001). After transplant, Black patients had higher levels of dd-cfDNA, 0.09% (interquartile range, 0.001–0.30) compared with White patients, 0.05% (interquartile range, 0.001–0.23; P =0.003). Beyond 6 months, Black patients showed a persistent rise in dd-cfDNA with higher levels compared with White patients. Cell-free mitochondrial DNA was higher in Black patients (185 788 copies/mL; interquartile range, 101 252–422 133) compared with White patients (133 841 copies/mL; interquartile range, 75 346–337 990; P <0.001). The primary composite outcome occurred in 43% and 55% of Black patients at 1 and 2 years, compared with 23% and 27% in White patients, P <0.001. In a multivariable model, Black patient race (hazard ratio, 2.61 [95% CI, 1.35–5.04]; P =0.004) and %dd-cfDNA (hazard ratio, 1.15 [95% CI, 1.03–1.28]; P =0.010) were associated with the primary composite outcome. CONCLUSIONS: Elevated dd-cfDNA and cell-free mitochondrial DNA after heart transplant may mechanistically be implicated in the higher incidence of AR and worse clinical outcomes in Black transplant recipients. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02423070.