Abstract: SA-PO478

Genome-Wide Association Meta-Analysis for Acute Rejection of Kidney Transplants

Session Information

Category: Transplantation

  • 1702 Transplantation: Clinical and Translational

Authors

  • Israni, Ajay K., Hennepin County Medical Center, Minneapolis, Minnesota, United States
  • Bakker, Stephan J.L., University Medical Center Groningen, Roden, Netherlands
  • Cavalleri, Gianpiero, RCSI, Dublin, Italy
  • Oetting, William S., University of Minnesota, Minneapolis, Minnesota, United States
  • Schladt, David P., Minneapolis Medical Research Foundation, Minneapolis, Minnesota, United States
  • Van setten, Jessica, UMC Utrecht, Utrecht, Netherlands
  • Kwok, Pui-Yan, UCSF, San Francisco, California, United States
  • Eikmans, Michael, Leiden University, Leiden , Netherlands
  • Snieder, Harold, University Medical Center Groningen, Roden, Netherlands
  • Wu, Baolin, University of Minnesota, Minneapolis, Minnesota, United States
  • Bassaganyas, Laia, University of California, San Francisco, San Francisco, California, United States
  • Jacobson, Pamala A., University of Minnesota, Minneapolis, Minnesota, United States
  • Yang, Jianxin, Leiden University, Leiden , Netherlands
  • Van der most, Peter Johannes, University of Groningen, Groningen, Netherlands
  • Asselbergs, Folkert W, University Medical Center Utrecht, Utrecht, Netherlands
  • Keating, Brendan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Guan, Weihua, University of Minnesota, Minneapolis, Minnesota, United States
  • Dorr, Casey R., Minneapolis Medical Research Foundation, Minneapolis, Minnesota, United States
  • De Borst, Martin H., University Medical Center Groningen, Roden, Netherlands
  • Stapleton, Caragh P., RCSI, Dublin, Italy
  • Phelan, Paul J., NHS Lothien, Edinburgh, United Kingdom
  • Conlon, Peter J., Beaumont Hospital, Dublin 9, Co Dublin, Ireland
  • Birdwell, Kelly A., Vanderbilt University, Nashville, Tennessee, United States

Group or Team Name

  • Kidney Group of iGeneTRAiN
Background

Acute rejection (AR) is associated with worse kidney allograft survival.

Methods

We performed a genome-wide association study (GWAS) meta-analysis of AR in recipients and donors after kidney transplantation using the Affymetrix exome plus chip. AR was defined by treating physician at anytime post-transplant. Genotype imputation was carried out based on the 1000 Genomes project and Genomes of The Netherlands reference datasets. The analysis was adjusted for age, sex, living versus deceased donors, and population stratification using principal components.

Results

The interim meta-analysis of 5 GWAS cohorts participating in iGeneTRAiN included 4,437 Caucasian kidney transplant recipients with 999 (23%) AR events (Table 1). Twenty-five recipient single-nucleotide polymorphisms (SNPs) reached GWAS significance (p < 1E-7) for their association with AR. The top four recipient SNPs with strongest AR association include two located in introns of MANSC1 rs12578158 (p =1.53E-9) and rs12580693 (p = 1.75E-9). Another is located 7.5 kb upstream of UGT2B10 rs294768 (p = 1.24E-8). The fourth SNP is located in the 3’UTR of NUB1 rs544144806 (p = 4.81E-8). Furthermore, 14 of the 25 top recipient SNPs are located in or near UGT2B10, including rs2942857, which is an mRNA splice acceptor. The donor analysis identified 66 SNPs reaching GWAS significance for their association with AR. The top two of these SNPs are rs8180830 (p = 2.90E-9) and rs77439859 (p = 3.69E-9) which are 79 kb and 58 kb upstream, respectively, of HERPUD2. Another donor SNP associated with AR is rs79865478 (p = 4.62E-8), located in an intron of SOX5.

Conclusion

We identified several novel susceptibility loci associated with AR, which can be validated by independent cohorts.

Kidney Genome-Wide Association Studies Included in the Meta-Analysis
Study NameN% Living DonorsAR Events
TransplantLines, Netherlands110623369
Ireland Cohort3150130
DeKAF Genomics, USA, Canada232960390
Liden2774245
Scripps4107665

Funding

  • Other NIH Support