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. 2024 May 31;19(5):e0303446.
doi: 10.1371/journal.pone.0303446. eCollection 2024.

Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch

Rui Cao  1 , David P Schladt  2 , Casey Dorr  2   3 , Arthur J Matas  4 , William S Oetting  5 , Pamala A Jacobson  5 , Ajay Israni  2   3 , Jinbo Chen  6 , Weihua Guan  1
Affiliations

Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch

Rui Cao et al. PLoS One. .

Abstract

Background: Acute rejection (AR) after kidney transplantation is an important allograft complication. To reduce the risk of post-transplant AR, determination of kidney transplant donor-recipient mismatching focuses on blood type and human leukocyte antigens (HLA), while it remains unclear whether non-HLA genetic mismatching is related to post-transplant complications.

Methods: We carried out a genome-wide scan (HLA and non-HLA regions) on AR with a large kidney transplant cohort of 784 living donor-recipient pairs of European ancestry. An AR polygenic risk score (PRS) was constructed with the non-HLA single nucleotide polymorphisms (SNPs) filtered by independence (r2 < 0.2) and P-value (< 1×10-3) criteria. The PRS was validated in an independent cohort of 352 living donor-recipient pairs.

Results: By the genome-wide scan, we identified one significant SNP rs6749137 with HR = 2.49 and P-value = 2.15×10-8. 1,307 non-HLA PRS SNPs passed the clumping plus thresholding and the PRS exhibited significant association with the AR in the validation cohort (HR = 1.54, 95% CI = (1.07, 2.22), p = 0.019). Further pathway analysis attributed the PRS genes into 13 categories, and the over-representation test identified 42 significant biological processes, the most significant of which is the cell morphogenesis (GO:0000902), with 4.08 fold of the percentage from homo species reference and FDR-adjusted P-value = 8.6×10-4.

Conclusions: Our results show the importance of donor-recipient mismatching in non-HLA regions. Additional work will be needed to understand the role of SNPs included in the PRS and to further improve donor-recipient genetic matching algorithms. Trial registry: Deterioration of Kidney Allograft Function Genomics (NCT00270712) and Genomics of Kidney Transplantation (NCT01714440) are registered on ClinicalTrials.gov.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Manhattan plot of the genome-wide scan in the DeKAF Genomics cohort.
Fig 2
Fig 2. The distribution of donor-recipient mismatching PRS scores in the DeKAF Genomics and GEN-03 cohorts.
Fig 3
Fig 3. Functional classification of the genes involved in donor-recipient mismatching PRS.
Fig 4
Fig 4. Results of over-representation test for the PRS genes.
See this image and copyright information in PMC

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