Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch.
<h4>Background</h4>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...
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0303446 |
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| author | Rui Cao David P Schladt Casey Dorr Arthur J Matas William S Oetting Pamala A Jacobson Ajay Israni Jinbo Chen Weihua Guan |
| author_facet | Rui Cao David P Schladt Casey Dorr Arthur J Matas William S Oetting Pamala A Jacobson Ajay Israni Jinbo Chen Weihua Guan |
| author_sort | Rui Cao |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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. |
| format | Article |
| id | doaj-art-999668b711c345a1a76402758a81e39e |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-999668b711c345a1a76402758a81e39e2025-01-17T05:32:01ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-01195e030344610.1371/journal.pone.0303446Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch.Rui CaoDavid P SchladtCasey DorrArthur J MatasWilliam S OettingPamala A JacobsonAjay IsraniJinbo ChenWeihua Guan<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.https://doi.org/10.1371/journal.pone.0303446 |
| spellingShingle | Rui Cao David P Schladt Casey Dorr Arthur J Matas William S Oetting Pamala A Jacobson Ajay Israni Jinbo Chen Weihua Guan Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch. PLoS ONE |
| title | Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch. |
| title_full | Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch. |
| title_fullStr | Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch. |
| title_full_unstemmed | Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch. |
| title_short | Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch. |
| title_sort | polygenic risk score for acute rejection based on donor recipient non hla genotype mismatch |
| url | https://doi.org/10.1371/journal.pone.0303446 |
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