Introduction:Despite higher survival rates of liver allograft recipients through improvements in post-transplant surgery treatments, acute cellular rejection (ACR) remains a frequent & significant complication impacting long-term allograft function & patient survival rates. ACR pathogenesis is complex, affected by many factors and additional genetic factors including minor-histocompatibility antigen (mHA) loci are suspected to underpin ACR. Genetic studies to date have been limited to candidate gene regions in moderate study sizes. Genome-wide association studies (GWAS) have been very successful in discovering genetic associations with a range of different diseases.

Methods: DNA was available for 1537 liver D-R pairs from 4 US-based cohorts: the A2ALL study; A-WISH study; Baylor University Medical Center, Dallas study; and UPenn Liver Transplant (BioTIP) studies. We tested associations between time to 1st biopsy proven rejection (BPR) using the TxArray, a genotyping array comprising >780,000 genome-wide markers with denser content in prioritized transplantation loci. Our loss-of-function (LoF) analyses pipeline also assessed human genes knocked out in 0, 1 or 2 copies in D-R pairs.

Results: Genetic distance, which empirically measures the global genetic ancestral backgrounds between all D-R pairs, was found to be associated with time to 1st BPR among Caucasian recipients (HR:2.58; 95%CI:1.04–6.37; p=0.04). After accounting for genetic distance, variants located within PLCB4 at 20p12 were significantly associated with time to 1st BPR (rs6056546, HR:2.06; 95%CI: 1.63–3.00; p=1.4×10^-9). Two additional genetic variants loci located in intergenic regions between MIR4275 & PCDH7 at 4p15, & downstream of CHRNA1 at 2q31 also reached GWAS significance. Furthermore, LoF analyses found 4 genes, OR2C1, UGT2A1, PSCA and CCDC88C to be associated with ACR.

Conclusions: Using GWAS & LoF analyses, we identified a number of statistically significant genetic signals for ACR in well-powered GWAS. Additional studies to replicate and fine-map these association signals and functional assessment of these genetic variants are also ongoing and may reveal fundament new insights into the biology of ACR in liver transplantation.

CITATION INFORMATION: Keating B, Chang B.-L, van Setten J, Cole B, Jennings L, Klintmalm G, Shaked A. Genome-Wide Genotyping in > 1500 Liver Allograft Recipient and Donor Pairs Reveals Several Associations with Acute Cellular Rejection. Am J Transplant. 2017;17 (suppl 3).

« Back to 2017 American Transplant Congress