Abstract: FR-PO1051

Genome-Wide Donor-Recipient Genetic Differences Influence Renal Allograft Survival Independent of HLA

Session Information

Category: Transplantation

  • 1702 Transplantation: Clinical and Translational

Authors

  • Menon, Madhav C., Mount Sinai School of Medicine, Forest Hills, New York, United States
  • Zhang, Zhongyang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Zhang, Weijia, Mount Sinai School of Medicine, Forest Hills, New York, United States
  • Stahl, Eli A., Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Hao, Ke, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Murphy, Barbara T., Icahn School of Medicine at Mount Sinai, New York, New York, United States
Background

Renal interstitial fibrosis (IF-TA) is a non-specific histologic entity identified in 30-40% of all allografts that fail. Transcriptomic studies of human allograft biopsies show that gene-signatures of ongoing alloimmune activity persist in these IF-TA lesions. Conventionally, anti-donor alloimmunity is attributed to HLA-mismatching. However, non-HLA loci have recently been shown to determine allo-recognition & responses.

Methods

We utilized unique genome-wide SNP array data encompassing Donor-Recipient pairs (D-R) from our recently completed multicenter GoCAR study [PI- Barbara Murphy] to study the role of D-R differences on death-censored allograft survival (DCGS) after excluding HLA-regions (n=385). We used ADMIXTURE analysis on genome-wide genotype data to plot the actual genomic race (AGR) of D-Rs using 1000-genome data (Fig-1). Long term survival data were obtained from UNOS/ANZDATA.

Results

AGR was more accurate than self-reported race (reclassifying 2.7-54% D-Rs among different races). Recipient AGR impacted DCGS in adjusted cox survival models (aHR-2.25 for African-American AGR), while donor AGR had minimal effect. Euclidean D-R genetic distance calculated from AGR significantly associated with DCGS. HLA-matching did not impact DCGS in adjusted analysis. In D-R pairs of similar ancestry, proportion of genome-shared identity-by-descent (pIBD), was predictive of allograft survival (n=224; Log rank P<0.01; pIBD<0.1 vs > 0.1). Notably, pIBD and AGR were not significantly associated with clinical/subclinical rejection at any time post-transplant. In multivariate analysis, lower pIBD scores strongly associated with histologic vascular intimal fibrosis and IF-TA in biopsies obtained less than 1-year (n=199; P<0.01). External validation of these results is ongoing.

Conclusion

Together our novel data show that non-HLA D-R differences determine vascular intimal fibrosis, IF-TA and impact allograft survival.

Funding

  • NIDDK Support