The genetic determinants of renal allograft rejection

Hernandez-Fuentes, Maria P.; Stapleton, Caragh; Cavalleri, Gianpiero L.; Conlon, Peter J.; Weale, Michael E.; Lord, Graham M.; Kingdom, United

doi:10.1111/ajt.14909

Cited by 6 publications

(6 citation statements)

References 5 publications

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“…There have also been associations with protection against allograft loss and NF‐κB1 . 109 A more comprehensive review of these associations is presented by Dorr et al 104 and Hernandez‐Fuentes et al 110 …”

Section: Primary (Naïve or De Novo) Allo‐immune Responsementioning

confidence: 99%

“…107,108 There have also been associations with protection against allograft loss and NF-κB1. 109 A more comprehensive review of these associations is presented by Dorr et al 104 and Hernandez-Fuentes et al 110 Despite a large body of published data, there is a lack of concordance across genetically varied transplant populations and with differences in disease phenotype definition such as serum creatinine or specific pathological diagnoses whose criteria change periodically. 111,112 Similarly, the effect of individual gene variants is generally relatively small, and it is likely that few are obligatory for the outcome to occur.…”

Section: Genetic Modifiers Of Alloimmunitymentioning

confidence: 99%

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Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

Tambur

Campbell

Chong

et al. 2020

American Journal of Transplantation

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Section: Primary (Naïve or De Novo) Allo‐immune Responsementioning

confidence: 99%

Section: Genetic Modifiers Of Alloimmunitymentioning

confidence: 99%

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

Tambur

Campbell

Chong

et al. 2020

American Journal of Transplantation

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“…Although the full extent of TNFRSF13B diversity and implications for physiology remain to be established (doing so will depend on meticulous sequencing of all exons and regulatory sequences), our results suggest the potential value. The need for full sequencing of polymorphic genes is highlighted by the failure of genome-wide association studies to identify TNFRSF13B SNPs as a risk factor for rejection ( 50 – 52 ).…”

Section: Discussionmentioning

confidence: 99%

TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells

Barbosa¹,

Lefferts²,

Huynh³

et al. 2021

JCI Insight

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Host genes define the severity of inflammation and immunity but specific loci doing so are unknown. Here we show that TNF receptor superfamily member 13B ( TNFRSF13B ) variants, which enhance defense against certain pathogens, also control immune-mediated injury of transplants, by regulating innate B cells’ functions. Analysis of TNFRSF13B in human kidney transplant recipients revealed that 33% of those with antibody-mediated rejection (AMR) but fewer than 6% of those with stable graft function had TNFRSF13B missense mutations. To explore mechanisms underlying aggressive immune responses, we investigated alloimmunity and rejection in mice. Cardiac allografts in Tnfrsf13b- mutant mice underwent early and severe AMR. The dominance and precocity of AMR in Tnfrsf13b -deficient mice were not caused by increased alloantibodies. Rather, Tnfrsf13b mutations decreased “natural” IgM and compromised complement regulation, leading to complement deposition in allografted hearts and autogenous kidneys. Thus, WT TNFRSF13B and Tnfrsf13b support innate B cell functions that limit complement-associated inflammation; in contrast, common variants of these genes intensify inflammatory responses that help clear microbial infections but allow inadvertent tissue injury to ensue. The wide variation in inflammatory reactions associated with TNFRSF13B diversity suggests polymorphisms could underlie variation in host defense and explosive inflammatory responses that sometimes enhance morbidity associated with immune responses.

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“…9 This highlights the need for larger, robust GWAS of allograft outcome to determine the extent to which common variation affects the outcome of kidney transplantation. 8 Neither the PTPRO or CCDC67 signal replicated in the UKIRTC GWAS of acute rejection; however, the definition of acute rejection in the UKIRTC study 11 was not specific to T cell-mediated rejection which may explain the discordance. A GWAS involving pooled DNA from 4127 renal transplant recipients identified signals of association with T cell-mediated acute rejection at the PTPRO and CCDC67 loci.…”

Section: Introductionmentioning

confidence: 98%

“…The finding was replicated, but not as part of an independent study. 8 Neither the PTPRO or CCDC67 signal replicated in the UKIRTC GWAS of acute rejection; however, the definition of acute rejection in the UKIRTC study 11 was not specific to T cell-mediated rejection which may explain the discordance. Here, we hypothesize that a continuous variable of outcome (ie, eGFR) would provide additional power to detect the impact of genetic variation on markers of graft outcome.…”

Section: Introductionmentioning

confidence: 98%

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

Genomics

2019

American Journal of Transplantation

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Genetic variation across the human leukocyte antigen loci is known to influence renal‐transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time‐points, out to 5 years posttransplantation. We conducted GWAS meta‐analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1‐year posttransplant. Thirty‐two percent of the variability in eGFR at 1‐year posttransplant was explained by our model containing clinical covariates (including weights for death/graft‐failure), principal components and combined donor‐recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables.

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The genetic determinants of renal allograft rejection

Cited by 6 publications

References 5 publications

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population

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