title: 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.
authors.affiliation: Bone Marrow Transplantation and Immune Deficiency, and.
authors.forename: Sonata
authors.initials: S
authors.lastname: Jodele
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
authors.forename: Kejian
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
authors.forename: Fanggeng
authors.initials: F
authors.lastname: Zou
authors.affiliation: Division of Nephrology, The Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Laskin
authors.affiliation: Bone Marrow Transplantation and Immune Deficiency, and.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Dandoy
authors.affiliation: Bone Marrow Transplantation and Immune Deficiency, and.
authors.forename: Kasiani C
authors.initials: KC
authors.lastname: Myers
authors.affiliation: Bone Marrow Transplantation and Immune Deficiency, and.
authors.forename: Adam
authors.initials: A
authors.lastname: Lane
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and Department of Environmental Health, Division of Biostatistics and Bioinformatics, University of Cincinnati, Cincinnati, OH.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Meller
authors.affiliation: Department of Environmental Health, Division of Biostatistics and Bioinformatics, University of Cincinnati, Cincinnati, OH.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Department of Environmental Health, Division of Biostatistics and Bioinformatics, University of Cincinnati, Cincinnati, OH.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chen
authors.affiliation: Bone Marrow Transplantation and Immune Deficiency, and.
authors.forename: Stella M
authors.initials: SM
authors.lastname: Davies
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D011446:Prospective Studies; D057049:Thrombotic Microangiopathies / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D059467:Transcriptome