Genome-wide association study for time to failure of kidney transplants from African American deceased donors |
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| Authors: | Jasmin Divers Lijun Ma William Mark Brown Nicholette D Palmer Young Choi Ajay K Israni Stephen O Pastan Bruce A Julian Robert S Gaston Pamela J Hicks Amber M Reeves-Daniel Barry I Freedman |
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| Institution: | 1. Division of Health Services Research, Department of Foundations of Medicine, NYU Long Island School of Medicine and NYU Winthrop Research Institute, Mineola, NY, USA;2. Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA;3. Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA;4. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA;5. Department of Medicine, Hennepin Healthcare, University of Minnesota, Minneapolis, MN, USA;6. Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA;7. University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA |
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| Abstract: | Two renal-risk variants in the apolipoprotein L1 gene (APOL1) in African American (AA) deceased donors (DD) are associated with shorter renal allograft survival after transplantation. To identify additional genes contributing to allograft survival, a genome-wide association study was performed in 532 AA DDs. Phenotypic data were obtained from the Scientific Registry of Transplant Recipients. Association and single-nucleotide polymorphism (SNP)-by-APOL1 interaction tests were conducted using death-censored renal allograft survival accounting for relevant covariates. Replication and inverse-variance-weighted meta-analysis were performed using data from 250 AA DD in the Genomics of Transplantation study. Accounting for APOL1, multiple SNPs near the Nudix Hydrolase 7 gene (NUDT7) showed strong independent effects (P = 1.6 × 10−8-2.2 × 10−8). Several SNPs in the Translocation protein SEC63 homolog (SEC63; P = 2 × 10−9-3.7 × 10−8) and plasmacytoma variant translocation 1 (PVT1) genes (P = 4.0 × 10−8-7 × 10−8) modified the effect of APOL1 on allograft survival. SEC63 is expressed in human renal tubule cells and glomeruli, and PVT1 is associated with diabetic kidney disease. Overall, associations were detected for 41 SNPs (P = 2 × 10−9-5 × 10−8) contributing independently or interacting with APOL1 to impact renal allograft survival after transplantation from AA DD. Given the small sample size of the discovery and replication sets, independent validations and functional genomic efforts are needed to validate these results. |
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| Keywords: | African Americans APOL1 chronic kidney disease graft failure genome-wide association study kidney transplantation |
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