APOL1 high‐risk genotypes and renal transplantation

Shah, Shachi; Shapiro, Ron; Murphy, Barbara; Menon, Madhav C.

doi:10.1111/ctr.13582

Cited by 9 publications

(6 citation statements)

References 64 publications

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“…The most compelling case for genetic testing of APOL1 in the clinical setting at present is therefore in kidney transplantation, particularly for potential living donors 64 , 65 . An ongoing NIH-funded study — the APOL1 Long-term Kidney Transplantation Outcomes study (APOLLO) — is aimed at prospectively determining outcomes in living kidney donors with African ancestry and in recipients of living and deceased donor kidneys from individuals with African ancestry, in order to better define the effect of APOL1 risk alleles on transplantation outcomes, and will provide data with which to guide patients and clinicians in judging the risk of transplantation for living donors and recipients 66 , 67 .…”

Section: Apol1 and Kidney Diseasementioning

confidence: 99%

The evolving story of apolipoprotein L1 nephropathy: the end of the beginning

et al. 2022

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Genetic coding variants in APOL1 , which encodes apolipoprotein L1 (APOL1), were identified in 2010 and are relatively common among individuals of sub-Saharan African ancestry. Approximately 13% of African Americans carry two APOL1 risk alleles. These variants, termed G1 and G2, are a frequent cause of kidney disease — termed APOL1 nephropathy — that typically manifests as focal segmental glomerulosclerosis and the clinical syndrome of hypertension and arterionephrosclerosis. Cell culture studies suggest that APOL1 variants cause cell dysfunction through several processes, including alterations in cation channel activity, inflammasome activation, increased endoplasmic reticulum stress, activation of protein kinase R, mitochondrial dysfunction and disruption of APOL1 ubiquitinylation. Risk of APOL1 nephropathy is mostly confined to individuals with two APOL1 risk variants. However, only a minority of individuals with two APOL1 risk alleles develop kidney disease, suggesting the need for a ‘second hit’. The best recognized factor responsible for this ‘second hit’ is a chronic viral infection, particularly HIV-1, resulting in interferon-mediated activation of the APOL1 promoter, although most individuals with APOL1 nephropathy do not have an obvious cofactor. Current therapies for APOL1 nephropathies are not adequate to halt progression of chronic kidney disease, and new targeted molecular therapies are in clinical trials.

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Section: Apol1 and Kidney Diseasementioning

confidence: 99%

The evolving story of apolipoprotein L1 nephropathy: the end of the beginning

et al. 2022

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“…Patients with African ancestry sustain a significantly higher risk of non-Mendelian focal segmental glomerulosclerosis (FSGS) as well as end stage kidney disease (ESKD) (reviewed in literature (1)). Seminal work identified the risk genotypes of Apolipoprotein L1 (APOL1) when present as two copies of either or both G1 and G2 alleles, (2) explained the increased risk of FSGS and ESRD observed in African Americans (AAs).…”

Section: Introductionmentioning

confidence: 99%

Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes

Zhang¹,

Sun²,

Fu³

et al. 2021

Journal of Clinical Investigation

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Apolipoprotein L1 (APOL1) risk-alleles in donor kidneys associate with graft loss but whether recipient risk-allele expression impacts transplant outcomes is unclear. To test whether recipient APOL1 risk-alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data of donors and recipients from two kidney transplant cohorts, Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation (CTOT1/17). We estimated genetic ancestry (quantified as proportion of African ancestry or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we observed that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), and within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with increased risk of any T cell-mediated rejection (TCMR) event. These associations were validated in CTOT1/17. Ex vivo studies of peripheral blood mononuclear cells revealed unanticipated high APOL1 expression in activated CD4 + /CD8 + T cells and natural killer cells. We detected enriched immune response gene pathways in risk-allele carriers vs. noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk-alleles associating with TCMR and DCAL. This finding has broader implications for immune mediated injury to native kidneys.

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“…Previous studies have also revealed that PENK is an important biomarker for renal dysfunction (42)(43)(44). In addition, APOL1, encoding a secreted high-density lipoprotein that binds to apolipoprotein A-I to promote lipid exchange, is reported to be associated with kidney disease when it is mutated (45). With regards to the interaction between the cardiovascular and renal systems, PenK and aPol1 are also of potential value for cardiac disease research (46).…”

Section: Discussionmentioning

confidence: 99%

Integrated microarray analysis to identify potential biomarkers and therapeutic targets in dilated cardiomyopathy

et al. 2020

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dilated cardiomyopathy (dcM) is a primary cardiomyopathy with high mortality. The aim of the present study was to identify the related genes in dcM. The four expression profiles (GSE17800, GSE21610, GSE42955 and GSE79962) downloaded from the Gene Expression Omnibus (GEO) database were analyzed using RankProd and metaMA R packages to identify differentially expressed genes (DEGs). DEGs were uploaded to the Database for Annotation, Visualization and Integrated Discovery (DAVID), for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. a protein-protein interaction (PPi) network of the DEGs was constructed using the STRING database. In addition, hub genes were identified using the Cytoscape plugin cytoHubba. A mouse DCM model, which established via intraperitoneal injection with doxorubicin (DOX), was used to validate the hub genes. A total of 898 DEGs were identified across the four microarrays. Furthermore, GO analysis demonstrated that these DEGs were mainly enriched in cell adhesion, negative regulation of cell proliferation, negative regulation of apoptotic process and potassium ion transport. in addition, KEGG analysis revealed that DEGs were mainly enriched in the ecM-receptor interaction, the p53 signaling pathway, cardiac muscle contraction and the hypoxia-inducible factor signaling pathway. Proenkephalin (PENK), chordin like 1 (CHRDL1), calumenin (CALU), apolipoprotein L1, insulin-like growth factor binding protein 3 (IGFBP3) and ceruloplasmin (CP) were identified as hub genes in the PPI network. Furthermore, the expression levels of PENK, CHRDL1, IGFBP3, CP and CALU in hearts with dcM were validated using a mouse model. in conclusion, the present study identified six hub genes related to dcM. Therefore, the present results may provide a potential mechanism for DCM involving these hub genes, which may serve as biomarkers for screening and diagnosis in the clinic.

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APOL1 high‐risk genotypes and renal transplantation

Cited by 9 publications

References 64 publications

The evolving story of apolipoprotein L1 nephropathy: the end of the beginning

The evolving story of apolipoprotein L1 nephropathy: the end of the beginning

Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes

Integrated microarray analysis to identify potential biomarkers and therapeutic targets in dilated cardiomyopathy

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