Integrative Analysis of ExomeSeq and Gene Expression Data for Identification of Novel Variants Associated with Antibody-Mediated Rejection in Kidney Transplant.
1Institute for Computational Health Science, University of California, San Francisco (UCSF), San Francisco, CA
2Department of Surgery, University of California, San Francisco (UCSF), University of California, San Francisco (UCSF), CA
3Department of Medicine, Johns Hopkins, Baltimore, MD
Meeting: 2017 American Transplant Congress
Abstract number: B61
Keywords: Genomics, Kidney transplantation, Rejection
Session Information
Session Name: Poster Session B: Antibody Mediated Rejection in Kidney Transplant Recipients II
Session Type: Poster Session
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 May 12, 2025.« Back to 2017 American Transplant Congress