Kidney Week

Abstract: TH-OR137

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

Session Information

• Policy and Pretransplant Considerations
  November 07, 2019 | Location: 151, Walter E. Washington Convention Center
  Abstract Time: 06:18 PM - 06:30 PM

Category: Transplantation

• 1902 Transplantation: Clinical

Authors

• Menon, Madhav C., Icahn School of Medicine at Mount Sinai, New York, New York, United States

Madhav C. Menon, MBBS, MD



Dr Menon is an Assistant Professor in Nephrology, and the Recanati Miller Transplant Institute at the Icahn school of Medicine at Mount Sinai. Dr Menon research interest is in novel mechanisms of renal allograft fibrosis and long term graft failure. This work has included Shroom3, a gene whose differential expression was shown to promote allograft fibrosis, but has pleiotropic effects in podocytes and tubular cells. Recent work is learning the role of non-MHC donor-recipient mismatches and chronic rejection and allograft damage utilizing translational human data and murine models.

• Zhang, Zhongyang, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Zhongyang Zhang,

• Sun, Zeguo, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Zeguo Sun,

• Zhang, Weijia, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Weijia Zhang,

• Hao, Ke, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Ke Hao,

• Murphy, Barbara T., Icahn School of Medicine at Mount Sinai, New York, New York, United States

Barbara T. Murphy,

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