Highlights
- •It is unclear if germline mutations in complement genes are associated with TA-TMA.
- •We performed a genetic association case-control study with 100 cases and 98 controls.
- •We did not observe rare variants in complement genes in association with TA-TMA.
- •29% TA-TMA and 33% controls had at least 1 rare variant in complement genes.
- •Rare variants in LRP1 (VWF clearance/oxidative stress) were associated with TA-TMA.
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
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Article info
Publication history
Published online: March 15, 2023
Accepted:
March 5,
2023
Received in revised form:
February 20,
2023
Received:
December 19,
2022
Identification
Copyright
© 2023 Elsevier Ltd. All rights reserved.
