Pathway-Driven Rare Germline Variants Associated With Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

Authors

Zhihui Zhang
Wei Hong
Qian Wu
Spiridon Tsavachidis
Jian-Rong Li
Christopher I Amos
Chao Cheng
Sarah E Sartain
Vahid Afshar-Kharghan
Jing-Fei Dong
Pavan Bhatraju
Paul J Martin
Robert S Makar
Pavan K Bendapudi
Ang Li

Publication Date

5-1-2023

Journal

Thrombosis Research

Abstract

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.

Keywords

Adult, Humans, Germ-Line Mutation, von Willebrand Factor, Hematopoietic Stem Cell Transplantation, Complement System Proteins, Thrombotic Microangiopathies, Germ Cells

Comments

Supplementary Materials

PMID: 36948020