Pathway-driven rare germline variants associated with transplant-associated thrombotic microangiopathy (TA-TMA).

Autor: Zhang Z; Institute for Clinical & Translational Research, Baylor College of Medicine, Houston, TX, United States of America., Hong W; Institute for Clinical & Translational Research, Baylor College of Medicine, Houston, TX, United States of America., Wu Q; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America., Tsavachidis S; Section of Epidemiology and Population Science, Baylor College of Medicine, Houston, TX, United States of America., Li JR; Institute for Clinical & Translational Research, Baylor College of Medicine, Houston, TX, United States of America., Amos CI; Institute for Clinical & Translational Research, Baylor College of Medicine, Houston, TX, United States of America; Section of Epidemiology and Population Science, Baylor College of Medicine, Houston, TX, United States of America., Cheng C; Institute for Clinical & Translational Research, Baylor College of Medicine, Houston, TX, United States of America., Sartain SE; Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States of America., Afshar-Kharghan V; Section of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America., Dong JF; BloodWorks Northwest Research Institute, Seattle, WA, United States of America., Bhatraju P; Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States of America., Martin PJ; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America; Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States of America., Makar RS; Division of Hematology and Blood Transfusion Service, Massachusetts General Hospital, Boston, MA, United States of America; Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA, United States of America., Bendapudi PK; Division of Hematology and Blood Transfusion Service, Massachusetts General Hospital, Boston, MA, United States of America; Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA, United States of America; Harvard Medical School, Boston, MA, United States of America., Li A; Section of Hematology-Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America. Electronic address: ang.li2@bcm.edu.
Jazyk: angličtina
Zdroj: Thrombosis research [Thromb Res] 2023 May; Vol. 225, pp. 39-46. Date of Electronic Publication: 2023 Mar 15.
DOI: 10.1016/j.thromres.2023.03.001
Abstrakt: The significance of rare germline mutations in transplant-associated thrombotic microangiopathy (TA-TMA) is not well studied. We performed a genetic association study in 100 adult TA-TMA patients vs. 98 post-transplant controls after matching by race, sex, and year. We focused on 5 pathways in complement, von Willebrand factor (VWF) function and related proteins, VWF clearance, ADAMTS13 function and related proteins, and endothelial activation (3641variants in 52 genes). In the primary analysis focused on 189 functional rare variants, no differential variant enrichment was observed in any of the pathways; specifically, 29 % TA-TMA and 33 % controls had at least 1 rare complement mutation. In the secondary analysis focused on 37 rare variants predicted to be pathogenic or likely pathogenic by ClinVar, Complement Database, or REVEL in-silico prediction tool, rare variants in the VWF clearance pathway were found to be significantly associated with TA-TMA (p = 0.008). On the gene level, LRP1 was the only one with significantly increased variants in TA-TMA in both analyses (p = 0.025 and 0.015). In conclusion, we did not find a significant association between rare variants in the complement pathway and TA-TMA; however, we discovered a new signal in the VWF clearance pathway driven by the gene LRP1 among likely pathogenic variants.
Competing Interests: Conflict of interest The authors declare no competing financial interests.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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