Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes
Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell-mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4+/CD8+ T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.
| Errataetall: |
CommentIn: Nat Rev Nephrol. 2021 Dec;17(12):794. - PMID 34667282 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:131 |
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| Enthalten in: |
The Journal of clinical investigation - 131(2021), 22 vom: 15. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Zhongyang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.12.2021 Date Revised 06.04.2022 published: Print CommentIn: Nat Rev Nephrol. 2021 Dec;17(12):794. - PMID 34667282 Citation Status MEDLINE |
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| doi: |
10.1172/JCI146643 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM330418815 |
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| 100 | 1 | |a Zhang, Zhongyang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Revised 06.04.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a CommentIn: Nat Rev Nephrol. 2021 Dec;17(12):794. - PMID 34667282 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell-mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4+/CD8+ T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Genetic variation | |
| 650 | 4 | |a Nephrology | |
| 650 | 4 | |a Organ transplantation | |
| 650 | 4 | |a T cells | |
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| 700 | 1 | |a Cravedi, Paolo |e verfasserin |4 aut | |
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| 700 | 1 | |a O'Connell, Philip J |e verfasserin |4 aut | |
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