Single nucleotide polymorphisms (SNPs) associated with acute Rejection in European
American kidney transplant recipients: A genome wide association study (GWAS)
Israni A1, Dorr C1, Miller MB2, Schladt D1, Sanghavi K3, Muthusamy A., Remmel RP4, Guan W 5,
Wu B5, Oetting WS3 , Jacobson, PA3, Matas, AJ6 for the DeKAF Genomics and GEN03
investigators
1
Department of Nephrology and Chronic Disease Research Group, Minneapolis Medical
Research Foundation, Hennepin County Medical Center
2
Department of Psychology, University of MN
3
Experimental and Clinical Pharmacology, College of Pharmacy, University of MN
4
Department of Medicinal Chemistry, College of Pharmacy, University of MN
5
Department of Biostatistics, University of MN
6
Department of Surgery, University of MN
Purpose: Acute rejection (AR) is associated with increased risk of allograft loss. Therefore, we
conducted a GWAS to determine SNPs associated with AR in a large, European American
cohort of (n=1,528) adult kidney or kidney pancreas transplant recipients in a 7-center
consortium.
Methods: European American kidney transplant recipients enrolled in the DeKAF Genomics
study and who received tacrolimus were genotyped using an exome-plus Affymetrix TXArray
chip containing 450,130 markers after QC. The associations between SNPs and AR were
evaluated using survival analysis.
Results: The median recipient age was 52.1 years (Interquartile range or IQR 42-61) yrs, 63%
were males and 67% received a living donor transplant. Median time to AR was 40 days
posttransplant (IQR 16-132). There were 240 AR events and 71% were cellular, 16% were
antibody mediated and 10% had features of both types of AR. The AR events were treated with
steroid only (57%), antibodies only (3%), steroids followed by antibodies (15%), antibodies and
steroids (18%) and other (6%).
No SNP showed genome-wide significance (p<5E-8). The two SNPs with smallest p-values are
rs146480420 and rs59677415 (p<8E-7) in EPCAM and small nucleolar RNA genes,
respectively. The top 83 SNPs with smallest p-values, were in the top canonical pathways such
as NF-kappaB activation, IL-8 signaling and leukocyte extravasation signaling.
Conclusion: SNPs in novel pathways had the smallest p-values in our cohort of European
Americans. Future meta-analysis with other cohorts is needed to identify less frequent SNPs
associated with AR.
This project was supported by grant number (5U19-AI070119 and 5U01-AI058013) from the
National Institute of Allergy and Infectious Disease.