Περίληψη:
Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that pretransplant genetic susceptibility is evident in adult TA-TMA and further investigated the association of TMA-associated variants with clinical outcomes. We studied 40 patients with TA-TMA, donors of 18 patients and 40 control non-TMA HCT recipients, without significant differences in transplant characteristics. Genomic DNA from pretransplant peripheral blood was sequenced for TMA-associated genes. Donors presented significantly lower frequency of rare variants and variants in exonic/splicing/untranslated region (UTR) regions, compared with TA-TMA patients. Controls also showed a significantly lower frequency of rare variants in ADAMTS13, CD46, CFH, and CFI. The majority of TA-TMA patients (31/40) presented with pathogenic or likely pathogenic variants. Patients refractory to conventional treatment (62%) and patients that succumbed to transplant-related mortality (65%) were significantly enriched for variants in exonic/splicing/UTR regions. In conclusion, increased incidence of pathogenic, rare and variants in exonic/splicing/UTR regions of TA-TMA patients suggests genetic susceptibility not evident in controls or donors. Notably, variants in exonic/splicing/UTR regions were associated with poor response and survival. Therefore, pretransplant genomic screening may be useful to intensify monitoring and early intervention in patients at high risk for TA-TMA. © 2020 Georg Thieme Verlag. All rights reserved.
Συγγραφείς:
Gavriilaki, E.
Touloumenidou, T.
Sakellari, I.
Batsis, I.
Mallouri, D.
Psomopoulos, F.
Tsagiopoulou, M.
Koutra, M.
Yannaki, E.
Papalexandri, A.
Taylor, P.
Nikolousis, E.
Stamouli, M.
Holbro, A.
Baltadakis, I.
Liga, M.
Spyridonidis, A.
Tsirigotis, P.
Charchalakis, N.
Tsakiris, D.A.
Brodsky, R.A.
Passweg, J.
Stamatopoulos, K.
Anagnostopoulos, A.
Λέξεις-κλειδιά:
ADAMTS13 gene; adult; allogeneic hematopoietic stem cell transplantation; Article; bioinformatics; bone marrow transplantation; CD46 gene; CFH gene; CFI gene; clinical outcome; controlled study; enzyme linked immunosorbent assay; follow up; gene; gene expression; gene mutation; gene sequence; genetic analysis; genetic association; genetic susceptibility; genotype; graft versus host reaction; hemolytic uremic syndrome; human; major clinical study; male; middle aged; mortality; overall survival; phenotype; plasma exchange; priority journal; single nucleotide polymorphism; thrombotic thrombocytopenic purpura; TMA gene; untranslated region; aged; allotransplantation; female; genetic predisposition; genetics; genome; genotype; hematologic disease; hematopoietic stem cell transplantation; postoperative complication; survival analysis; thrombotic thrombocytopenic purpura; young adult, ADAMTS13 protein, human; von Willebrand factor cleaving proteinase, ADAMTS13 Protein; Adult; Aged; Female; Genetic Predisposition to Disease; Genome; Genotype; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Postoperative Complications; Survival Analysis; Thrombotic Microangiopathies; Transplantation, Homologous; Untranslated Regions; Young Adult
