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Abstract: TH-OR137

Genome-Wide Non-HLA Donor-Recipient Mismatches in Intronic Regions Independently Associate with Graft Survival

Session Information

Category: Transplantation

  • 1902 Transplantation: Clinical

Authors

  • Menon, Madhav C., Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Zhang, Zhongyang, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Sun, Zeguo, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Zhang, Weijia, 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

Donor-recipient (D-R) mismatches at human leukocyte antigen (HLA) loci are used for management decisions. Recent work has showed the role of global non-HLA D-R mismatches, specifically exonic loci within genes coding transmembrane and secreted proteins in graft survival in Caucasian deceased donor cohorts. Since non-coding regions constitute ~98% of human genome, and these elements have demonstrable regulatory activity, we hypothesized that non-coding D-R genetic differences could also contribute to unchecked alloimmunity impacting graft survival.

Methods

We utilized genome-wide SNP array data on all D-Rs in the GOCAR study excluding HLA region (n=385 D-Rs). We quantified the genome-wide numbers of mismatches of all SNPs , and annotated those in non-coding regions, or exomes [divided further into nonsynonymous within genes coding transmembrane and secreted proteins] - all as separate continuous variables. Long-term death censored graft loss [DCGL] data were from UNOS/ANZDATA.

Results

Our multi-ethnic D-R cohort represented greater genetic diversity and included living donors vs published data. There were 73 DCGL events during median follow-up of 1824 days (IQR: 1392-2188 days).Genome-wide- & Tm-mismatches were all increased in inter-race vs intra-race transplants (p<0.001). The total numbers of SNP mismatches quantified as quartiles respectively impacted DCGL & all-cause GL in adjusted Cox models [Fig. 1A-B]. However, in multivariate Cox models after adjusting for protein-coding mismatches, non-coding D-R mismatches remained independently associated with graft survival. Surprisingly, non-HLA mismatch variables had no association with acute T-cell mediated rejection phenotypes (subclinical or clinical; with/without borderline lesions) in regression models.

Conclusion

Our data from a multi-ethnic cohort compliments recent work supporting the role of non-HLA D-R mismatches in long term allograft survival. In addition, we showed that non-coding loci based mismatches had independent impact on graft survival.

Funding

  • Other NIH Support