Kidney Week

Abstract: FR-OR083

GWAS of Time to Renal Allograft Failure after Transplantation of African American Deceased-Donor Kidneys

Session Information

• Rejection or Infection: Walking the Fine Line
  November 03, 2017 | Location: Room 394, Morial Convention Center
  Abstract Time: 05:30 PM - 05:42 PM

Category: Transplantation

• 1702 Transplantation: Clinical and Translational

Authors

• Divers, Jasmin, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

Jasmin Divers, PhD

https://www.phs.wakehealth.edu/public/profile.cfm?staffid=D67FF3EB-4D6C-491D-8BD3-2B835672CE35

• Ma, Lijun, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

Lijun Ma,

• Brown, William Mark, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

William Mark Brown,

• Palmer, Nicholette D, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

Nicholette D Palmer,

• Israni, Ajay K., Hennepin County Medical Center, Minneapolis, Minnesota, United States

Ajay K. Israni,

• Pastan, Stephen O., Emory University School of Medicine, Atlanta, Georgia, United States

Stephen O. Pastan,

• Julian, Bruce A., University of Alabama at Birmingham , Birmingham, Alabama, United States

Bruce A. Julian,

• Gaston, Robert S., University of Alabama at Birmingham , Birmingham, Alabama, United States

Robert S. Gaston,

• Hicks, Pamela J., Wake Forest Baptist Health, Winston Salem, North Carolina, United States

Pamela J. Hicks,

• Reeves-Daniel, Amber M., Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

Amber M. Reeves-Daniel,

• Freedman, Barry I., Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

Barry I. Freedman,

Background

Two apolipoprotein L1 gene (APOL1) renal-risk variants in African American (AA) deceased donors (DD) associate with shorter renal allograft survival after transplantation. Modifying factors are likely involved because not all deceased donor kidney transplants (DDKT) from AA donors with APOL1 risk genotypes fail early.

Methods

To identify genes contributing to allograft failure in addition to APOL1, a genome-wide association study (GWAS) was performed using the Illumina 5M chip in 477 AA DD, yielding 880 DDKTs. Association tests were performed using Cox proportional hazard on the genotyped and 1000 Genomes-imputed markers, using death-censored allograft survival as the outcome with each single nucleotide polymorphism (SNP), and accounting for donor African ancestry proportion, sex and age, and recipient sex, age, HLA match, cold ischemia time and peak panel reactive antibodies, using data collected from the Scientific Registry of Transplant Recipients (SRTR). SNP-by-APOL1 interaction effects on allograft survival were also assessed.

Results

Seven SNPs near the Nudix Hydrolase 7(NUDT7) gene, a coenzyme A diphosphatase, were among the top hits showing independent effects after accounting for APOL1 (p=1.6x10^-8 -3.8x10^-8). NUDT7 is expressed in human renal tubule cells. Two SNPs in the SEC63 gene modified the effect of APOL1 on allograft survival (interaction p=2x10^-9 - 3.7x10^-8). SEC63 encodes a protein translocation regulator, which appears at the endoplasmic reticulum (ER) and ER-mitochondria contact sites, and is expressed in human renal tubules and glomeruli.

Conclusion

Genetic associations were detected with 41 SNPs (p= 2x10^-9 - 5x10^-8) contributing independently or interacting with APOL1 to impact renal allograft survival after DDKT from AA deceased donors. Replication and functional validation efforts are needed to elucidate these associations.

Funding

• Other NIH Support