Association Between Donor-Recipient Genetic Matching and Acute Rejection in Kidney Transplantation

R. Cao¹, V. Arthur², J. Chen², B. Keating², C. Dorr³, D. Schladt³, G. Onyeaghala³, R. Mannon⁴, A. Matas¹, R. Remmel¹, N. Pankratz¹, B. Wu¹, W. Oetting¹, P. Jacobson¹, A. Israni³, W. Guan¹

¹University of Minnesota, Minneapolis, MN, ²University of Pennsylvania, Philadelphia, PA, ³Hennepin Healthcare Research Institute, Minneapolis, MN, ⁴University of Nebraska, Omaha, NE

Meeting: 2021 American Transplant Congress

Abstract number: 500

Keywords: Genomic markers, Kidney transplantation, Rejection

Topic: Basic Science » Acute Rejection

Session Information

Session Name: Acute Rejection

Session Type: Poster Abstract

Session Date & Time: None. Available on demand.

Location: Virtual

*Purpose: In this study we carried out a genome-wide association study (GWAS) between donor-recipient matching scores at individual SNP level and Acute rejection (AR) in kidney allograft recipients, aiming at finding potential genetic regions which are associated with AR posttransplant.

*Methods: Recipients with European ancestry from the Deterioration of Kidney Allograft Function (DeKAF) Genomics were analyzed with their matched living donors (n = 784 pairs). All donors except one were with European ancestry. The study evaluated AR events (n=161) post-kidney transplantation. Donor-recipient matching score was defined by the identify-by-state (IBS) between donor and recipient genotypes. Association between matching scores and AR was tested using Cox regression, adjusting for recipient age at transplantation, gender, prior non-kidney transplantation, and PRA (positive or negative). Bonferroni correction was applied to control for multiple testing.

*Results: There were 13 single-nucleotide polymorphisms (SNPs) at which donor-recipient matching scores were significantly associated with AR (p<5E-08). The strongest association was observed for an intronic variant rs6749137 (p=1.78E-09), which is located in the CPS1 gene region. The CPS1 gene codes a mitochondrial enzyme which catalyzes synthesis of carbamoyl phosphate from ammonia and bicarbonate, important in the removal of excess urea from cells. Other associated gene regions include SOX6 and CNOT6 (Table 1).

*Conclusions: We identified novel variants beyond human leukocyte antigen (HLA) region where the matching between donor and recipient was associated with AR. The results need to be further validated in external cohorts. Functional analysis of these SNPs will be required. Identification of genetic regions besides the HLA region will improve matching between kidney transplant recipients and their donors, and achieve beneficial outcome post-transplant.

Table 1: Top SNPs that were associated with AR in Kidney Transplant Donor-Recipient Matching
Chromosome: Base location	SNP	Reference allele : Alternate allele	Minor allele frequency	Gene	Functional annotation	Hazard Rate	P-Value
chr2:211541165	rs6749137	G:A	0.068	CPS1	Intronic	2.639	1.78E-09
chr22:44126517	rs73174346	C:T	0.090	EFCAB6	Intronic	2.487	4.90E-09
chr11:16520587	rs4573649	T:C	0.126	SOX6	Intronic	2.204	2.69E-08
chr4:78733015	rs10050214	G:T	0.153	CNOT6L	Intronic	2.041	2.89E-08
chr17:4673185	rs17824149	A:G	0.065	TM4SF5	Upstream transcript variant	2.441	3.27E-08
chr17:12928324	rs147435965:12928324	G:GTGTGTC	0.051	**	**	2.535	3.63E-08

To cite this abstract in AMA style:

Cao R, Arthur V, Chen J, Keating B, Dorr C, Schladt D, Onyeaghala G, Mannon R, Matas A, Remmel R, Pankratz N, Wu B, Oetting W, Jacobson P, Israni A, Guan W. Association Between Donor-Recipient Genetic Matching and Acute Rejection in Kidney Transplantation [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/association-between-donor-recipient-genetic-matching-and-acute-rejection-in-kidney-transplantation/. Accessed November 21, 2024.

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