TY - JOUR
T1 - Pathway-driven rare germline variants associated with transplant-associated thrombotic microangiopathy (TA-TMA)
AU - Zhang, Zhihui
AU - Hong, Wei
AU - Wu, Qian
AU - Tsavachidis, Spiridon
AU - Li, Jian rong
AU - Amos, Christopher I.
AU - Cheng, Chao
AU - Sartain, Sarah E.
AU - Afshar-Kharghan, Vahid
AU - Dong, Jing fei
AU - Bhatraju, Pavan
AU - Martin, Paul J.
AU - Makar, Robert S.
AU - Bendapudi, Pavan K.
AU - Li, Ang
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
KW - Complement system proteins
KW - Genetic association studies
KW - Hematopoietic stem cell transplantation
KW - Thrombotic microangiopathies
KW - von Willebrand factor
UR - http://www.scopus.com/inward/record.url?scp=85150385867&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85150385867&partnerID=8YFLogxK
U2 - 10.1016/j.thromres.2023.03.001
DO - 10.1016/j.thromres.2023.03.001
M3 - Article
C2 - 36948020
AN - SCOPUS:85150385867
SN - 0049-3848
VL - 225
SP - 39
EP - 46
JO - Thrombosis Research
JF - Thrombosis Research
ER -