The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy.

Abstract:

:Transplant-associated thrombotic microangiopathy (TA-TMA) occurs frequently after hematopoietic stem cell transplantation (HSCT) and can lead to significant morbidity and mortality. There are no data addressing individual susceptibility to TA-TMA. We performed a hypothesis-driven analysis of 17 candidate genes known to play a role in complement activation as part of a prospective study of TMA in HSCT recipients. We examined the functional significance of gene variants by using gene expression profiling. Among 77 patients undergoing genetic testing, 34 had TMA. Sixty-five percent of patients with TMA had genetic variants in at least one gene compared with 9% of patients without TMA (P < .0001). Gene variants were increased in patients of all races with TMA, but nonwhites had more variants than whites (2.5 [range, 0-7] vs 0 [range, 0-2]; P < .0001). Variants in ≥3 genes were identified only in nonwhites with TMA and were associated with high mortality (71%). RNA sequencing analysis of pretransplantation samples showed upregulation of multiple complement pathways in patients with TMA who had gene variants, including variants predicted as possibly benign by computer algorithm, compared with those without TMA and without gene variants. Our data reveal important differences in genetic susceptibility to HSCT-associated TMA based on recipient genotype. These data will allow prospective risk assessment and intervention to prevent TMA in highly susceptible transplant recipients. Our findings may explain, at least in part, racial disparities previously reported in transplant recipients and may guide treatment strategies to improve outcomes.

journal_name

Blood

journal_title

Blood

authors

Jodele S,Zhang K,Zou F,Laskin B,Dandoy CE,Myers KC,Lane A,Meller J,Medvedovic M,Chen J,Davies SM

doi

10.1182/blood-2015-08-663435

subject

Has Abstract

pub_date

2016-02-25 00:00:00

pages

989-96

issue

8

eissn

0006-4971

issn

1528-0020

pii

blood-2015-08-663435

journal_volume

127

pub_type

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