Date: Sunday, April 30, 2017
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall D1
Background: The objective of this work is to characterize the impact of the donor-recipient (D/R) HLA and non-HLA mismatches on the risk of antibody-mediated rejection (AMR).
Methods: Exome sequencing was performed in 55 DNA samples from 27 kidney tx recipients from 28 kidney donors (14 AMR, 7 Cell-mediated rejection (CMR) and 7 No Rejection (No-Rej) recipients). Variant mismatches were evaluated between D/R pairs for association with AMR using fisher exact test between the variant mismatch and the clinical endpoint. Using public genomic data, variants were annotated for genes up-regulated and/or highly expressed in kidney (2,786) and blood vessels (3,291), immune related genes (6,503) and cell surface genes (1,492) and further analyzed by pathway clustering analysis.
Results: We identified 472,502 variants that mismatched in at least one pair (388,437 in AMR, 270,757 in CMR and 249,601 in No-Rej). These differences were significantly associated with a decreased number of mismatched variants from the AMR to No-Rej group (P = 0.04). We found 98 variants (11 nonsynonymous) in 73 genes that were selected for significance as associated with AMR (OR>1, p<0.001). They were enriched for kidney (P = 5,3*10-3), blood vessels (P = 1.0*10-3), immune related genes (P = 1,2*10-1) and surface expressed proteins (P = 1.1*10-9). We identified different pathway clusters with an Enrichment Score (ES) ≥ 1.3.
Conclusions: The diagnosis of AMR of a kidney transplant might be improved by detecting the recipient's antibody response to potentially immunogenic non-HLA targets. While additional validation and replication is needed, we show that genetic differences between D/R pairs may have an impact in the outcome after organ transplantation. Further validation of the 73 AMR-specific variants are underway to evaluate if these also impact responses to specific non-HLA antibody responses that can be detected prior to full-blown AMR.
CITATION INFORMATION: Pineda S, Sigdel T, Jackson A, Sirota M, Sarwal M. Integrative Analysis of ExomeSeq and Gene Expression Data for Identification of Novel Variants Associated with Antibody-Mediated Rejection in Kidney Transplant. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Pineda S, Sigdel T, Jackson A, Sirota M, Sarwal M. Integrative Analysis of ExomeSeq and Gene Expression Data for Identification of Novel Variants Associated with Antibody-Mediated Rejection in Kidney Transplant. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/integrative-analysis-of-exomeseq-and-gene-expression-data-for-identification-of-novel-variants-associated-with-antibody-mediated-rejection-in-kidney-transplant/. Accessed November 23, 2020.
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