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Search results for: APOL1


#34514214   2021/06/19 To Up

Collapsing Glomerulopathy in Identical Twins With Lupus and High-Risk Apolipoprotein L1 () Genotype.

Margaret DeOliveira, Colby Feeney, Caroline Leahy, Sarah Nystrom, David N Howell, Samira S Farouk, Ming Wu, Opeyemi A Olabisi, Matthew A Sparks

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#34513880   2021/08/27 To Up

HIV Viremia Is Associated With Variants and Reduced JC-Viruria.

Variants in the () gene (G1-rs60910145, rs73885319, G2-rs71785313) are common in Africans and in individuals of recent African ancestry and are associated with an increased risk of non-diabetic chronic kidney disease (CKD) and in particular of HIV associated nephropathy (HIVAN). In light of the significantly increased risk of HIVAN in carriers of two risk alleles, a role in HIV infectivity has been postulated in the mechanism of associated kidney disease. Herein, we aim to explore the association between HIV viremia and genotype. In addition, we investigated interaction between BK and JC viruria, CKD and HIV viremia. A total of 199 persons living with HIV/AIDS (comprising 82 CKD cases and 117 controls) from among the participants in the ongoing Human Heredity and Health in Africa (H3Africa) Kidney Disease Research Network case control study have been recruited. The two renal risk alleles (RRA) genotypes were associated with a higher risk of CKD (OR 12.6, 95% CI 3.89-40.8, < 0.0001). Even a single APOL1 RRA was associated with CKD risk (OR 4.42, 95% CI 1.49-13.15, = 0.007). The 2 APOL1 RRA genotypes were associated with an increased probability of having HIV viremia (OR 2.37 95% CI 1.0-5.63, = 0.05). HIV viremia was associated with increased CKD risk (OR 7.45, 95% CI 1.66-33.35, = 0.009) and with a significant reduction of JC virus urine shedding (OR 0.35, 95% CI 0.12-0.98, = 0.046). In contrast to prior studies, JC viruria was not associated with CKD but was restricted in patients with HIV viremia, regardless of CKD status. These findings suggest a role of variants in HIV infectivity and emphasize that JC viruria can serve as biomarker for innate immune system activation.
Etty Kruzel-Davila, Barbara Mensah Sankofi, Ernestine Kubi Amos-Abanyie, Anita Ghansah, Alexander Nyarko, Seth Agyemang, Gordon A Awandare, Moran Szwarcwort-Cohen, Anat Reiner-Benaim, Basem Hijazi, Ifeoma Ulasi, Yemi Raheem Raji, Vincent Boima, Charlotte Osafo, Victoria May Adabayeri, Michael Matekole, Timothy O Olanrewaju, Samuel Ajayi, Manmak Mamven, Sampson Antwi, Adebowale D Ademola, Jacob Plange-Rhule, Fatiu Arogundade, Priscilla Abena Akyaw, Cheryl A Winkler, Babatunde L Salako, Akinlolu Ojo, Karl Skorecki, Dwomoa Adu

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#34499625   2021/09/09 To Up

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 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. non-carriers 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.
Zhongyang Zhang, Zeguo Sun, Jia Fu, Qisheng Lin, Khadija Banu, Kinsuk Chauhan, Marina Planoutene, Chengguo Wei, Fadi Salem, Zhengzi Yi, Ruijie Liu, Paolo Cravedi, Haoxiang Cheng, Ke Hao, Philip J O'Connell, Shuta Ishibe, Weijia Zhang, Steven G Coca, Ian W Gibson, Robert B Colvin, John C He, Peter S Heeger, Barbara T Murphy, Madhav C Menon

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#34449991   // To Up

Relative Contribution of Genetic and Environmental Factors in CKD.

Chronic kidney disease affects nearly 15 percent of the U.S. population. Onset and rate of progression are influenced by a combination of genetic and non-genetic factors. Because health care systems across the U.S. are beginning to deploy automated decision support to stratify patients at risk, we review the relative impact of genetic factors (e.g., APOL1 gene polymorphisms) and non-genetic factors (e.g., clinical comorbidities and exposure to environmental nephrotoxins) contributing to this common disease. Overall, the impact of non-genetic factors appears to exceed the impact of genetic factors.
Derek E Lee, Mohammad Qamar, Russell A Wilke

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#34440683   2021/07/28 To Up

Novel Human Podocyte Cell Model Carrying G2/G2 APOL1 High-Risk Genotype.

Apolipoprotein L1 () high-risk genotypes (HRG), G1 and G2, increase the risk of various non-diabetic kidney diseases in the African population. To date, the precise mechanisms by which risk variants induce injury on podocytes and other kidney cells remain unclear. Trying to unravel these mechanisms, most studies have used animal or cell models created by gene editing. We developed and characterised conditionally immortalised human podocyte cell lines derived from urine of a donor carrying HRG G2/G2. Following induction of APOL1 expression by polyinosinic-polycytidylic acid (poly(I:C)), we assessed functional features of APOL1-induced podocyte dysfunction. As control, APOL1 wild type (G0/G0) podocyte cell line previously generated from a Caucasian donor was used. Upon exposure to poly(I:C), G2/G2 and G0/G0 podocytes upregulated APOL1 expression resulting in podocytes detachment, decreased cells viability and increased apoptosis rate in a genotype-independent manner. Nevertheless, G2/G2 podocyte cell lines exhibited altered features, including upregulation of CD2AP, alteration of cytoskeleton, reduction of autophagic flux and increased permeability in an in vitro model under continuous perfusion. The human APOL1 G2/G2 podocyte cell model is a useful tool for unravelling the mechanisms of APOL1-induced podocyte injury and the cellular functions of APOL1.
Pepe M Ekulu, Oyindamola C Adebayo, Jean-Paul Decuypere, Linda Bellucci, Mohamed A Elmonem, Agathe B Nkoy, Djalila Mekahli, Benedetta Bussolati, Lambertus P van den Heuvel, Fanny O Arcolino, Elena N Levtchenko

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#34366528   2021/08/03 To Up

[Ig a vasculitis with nephritis (henoch-schönlein purpura) after covid-19: a case series and review of the literature.]

COVID-19 most related glomerular disease to date seems to be collapsing glomerulopathy, mostly in young Afroamerican patients with APOL1 gene risk alleles. However, in our population, predominant in elderly Caucasian patients, most biopsied pathology since the beginning of the pandemic has been IgA nephritis or Schönlein-Henoch purpura.Since the description of the first case of this entity after SARS-CoV-2 infection by our research group, three more cases have arisen, which are described in the following article. In contrast to the rest of IgA vasculitis cases reported, our patients presented more renal function deterioration and all of them required immunosupresive therapy. Moreover, some showed incomplete recovery of renal function.This case series strengthens the hypothesis that SARS-CoV-2 infection may be another trigger of this pathology.
Irene Oñate, Milagros Ortiz, Andrea Suso, Carmen Mon, Karen Galindo, Carolina Lentisco, Rosa Camacho, María Sánchez, Aniana Oliet, Olimpia Ortega, Juan C Herrero, José A Cortés, Alejandro Pascual

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#34352311   2021/08/03 To Up

A multi-center retrospective cohort study defines the spectrum of kidney pathology in Coronavirus 2019 Disease (COVID-19).

Kidney failure is common in patients with Coronavirus Disease-19 (COVID-19), resulting in increased morbidity and mortality. In an international collaboration, 284 kidney biopsies were evaluated to improve understanding of kidney disease in COVID-19. Diagnoses were compared to five years of 63,575 native biopsies prior to the pandemic and 13,955 allograft biopsies to identify diseases that have increased in patients with COVID-19. Genotyping for APOL1 G1 and G2 alleles was performed in 107 African American and Hispanic patients. Immunohistochemistry for SARS-CoV-2 was utilized to assess direct viral infection in 273 cases along with clinical information at the time of biopsy. The leading indication for native biopsy was acute kidney injury (45.4%), followed by proteinuria with or without concurrent acute kidney injury (42.6%). There were more African American patients (44.6%) than patients of other ethnicities. The most common diagnosis in native biopsies was collapsing glomerulopathy (25.8%), which was associated with high-risk APOL1 genotypes in 91.7% of cases. Compared to the five-year biopsy database, the frequency of myoglobin cast nephropathy and proliferative glomerulonephritis with monoclonal IgG deposits was also increased in patients with COVID-19 (3.3% and 1.7%, respectively), while there was a reduced frequency of chronic conditions (including diabetes mellitus, IgA nephropathy, and arterionephrosclerosis) as the primary diagnosis. In transplants, the leading indication was acute kidney injury (86.4%), for which rejection was the predominant diagnosis (61.4%). Direct SARS-CoV-2 viral infection was not identified. Thus, our multi-center large case series identified kidney diseases that disproportionately affect patients with COVID-19 and demonstrated a high frequency of APOL1 high-risk genotypes within this group, with no evidence of direct viral infection within the kidney.
Rebecca M May, Clarissa Cassol, Andrew Hannoudi, Christopher P Larsen, Edgar Lerma, Randy S Haun, Juarez R Braga, Samar I Hassen, Jon Wilson, Christine VanBeek, Mahesha Vankalakunti, Lilli Barnum, Patrick D Walker, T David Bourne, Nidia C Messias, Josephine M Ambruzs, Christie L Boils, Shree S Sharma, L Nicholas Cossey, Pravir V Baxi, Matthew Palmer, Jonathan Zuckerman, Vighnesh Walavalkar, Anatoly Urisman, Alexander Gallan, Laith F Al-Rabadi, Roger Rodby, Valerie Luyckx, Gustavo Espino, Srivilliputtur Santhana-Krishnan, Brent Alper, Son G Lam, Ghadeer N Hannoudi, Dwight Matthew, Mark Belz, Gary Singer, Srikanth Kunaparaju, Deborah Price, Saurabh Chawla, Chetana Rondla, Mazen A Abdalla, Marcus L Britton, Subir Paul, Uday Ranjit, Prasad Bichu, Sean R Williamson, Yuvraj Sharma, Ariana Gaspert, Philipp Grosse, Ian Meyer, Brahm Vasudev, Mohamad El Kassem, Juan Carlos Q Velez, Tiffany N Caza

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#34350953   2021/08/05 To Up

Recessive, gain-of-function toxicity in an APOL1 BAC transgenic mouse model mirrors human APOL1 kidney disease.

People of recent sub-Saharan African ancestry develop kidney failure much more frequently than other groups. A large fraction of this disparity is due to two coding sequence variants in the APOL1 gene. Inheriting two copies of these APOL1 risk variants, known as G1 and G2, causes high rates of focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy and hypertension-associated end-stage kidney disease. Disease risk follows a recessive mode of inheritance, which is puzzling given the considerable data that G1 and G2 are toxic gain-of-function variants. We developed coisogenic bacterial artificial chromosome (BAC) transgenic mice harboring either the wild-type (G0), G1 or G2 forms of human APOL1. Expression of interferon gamma (IFN-γ) via plasmid tail vein injection results in upregulation of APOL1 protein levels together with robust induction of heavy proteinuria and glomerulosclerosis in G1/G1 and G2/G2 but not G0/G0 mice. The disease phenotype was greater in G2/G2 mice. Neither heterozygous (G1/G0 or G2/G0) risk variant mice nor hemizygous (G1/-, G2/-) mice had significant kidney injury in response to IFN-γ, although the heterozygous mice had a greater proteinuric response than the hemizygous mice, suggesting that the lack of significant disease in humans heterozygous for G1 or G2 is not due to G0 rescue of G1 or G2 toxicity. Studies using additional mice (multicopy G2 and a non-isogenic G0 mouse) supported the notion that disease is largely a function of the level of risk variant APOL1 expression. Together, these findings shed light on the recessive nature of APOL1-nephropathy and present an important model for future studies.
Gizelle M McCarthy, Angelo Blasio, Olivia G Donovan, Lena B Schaller, Althea Bock-Hughes, Jose M Magraner, Jung Hee Suh, Calum F Tattersfield, Isaac E Stillman, Shrijal S Shah, Zsuzsanna K Zsengeller, Balajikarthick Subramanian, David J Friedman, Martin R Pollak

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#34341330   2021/08/02 To Up

Oncogene APOL1 promotes proliferation and inhibits apoptosis via activating NOTCH1 signaling pathway in pancreatic cancer.

APOL1 encodes a secreted high-density lipoprotein, which has been considered as an aberrantly expressed gene in multiple cancers. Nevertheless, the role of APOL1 in the regulatory mechanisms of pancreatic cancer remains unknown and should be explored. We identified APOL1 was abnormally elevated in human pancreatic cancer tissues compared with that in adjacent tissues and was associated with poor prognosis. The effects of APOL1 in PC cell proliferation, cell cycle, and apoptosis was verified via functional in vitro and in vivo experiments. The results showed that knockdown of APOL1 significantly inhibited the proliferation and promoted apoptosis of pancreatic cancer. In addition, we identified APOL1 could be a regulator of NOTCH1 signaling pathway using bioinformatics tools, qRT-PCR, dual-luciferase reporter assay, and western blotting. In summary, APOL1 could function as an oncogene to promote proliferation and inhibit apoptosis through activating NOTCH1 signaling pathway expression in pancreatic cancer; therefore, it may act as a novel therapeutic target for pancreatic cancer.
Jiewei Lin, Zhiwei Xu, Junjie Xie, Xiaxing Deng, Lingxi Jiang, Hao Chen, Chenghong Peng, Hongwei Li, Jiaqiang Zhang, Baiyong Shen

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#34331942   2021/07/28 To Up

Coiled-coil binding of the leucine zipper domains of APOL1 is necessary for the open cation channel conformation.

Apolipoprotein L-I (APOL1) is a channel-forming component necessary for innate immunity. The common human APOL1 variant G0 provides protection against infection with certain Trypanosoma and Leishmania parasite species, but it cannot protect against the trypanosomes responsible for human African trypanosomiasis (HAT). Human APOL1 variants G1 and G2 protect against human-infective trypanosomes, but also confer a higher risk of developing chronic kidney disease. Trypanosome-killing activity is dependent on the ability of APOL1 to insert into membranes at acidic pH and form pH-gated cation channels. We previously mapped the channel's pore-lining region to the C-terminal domain (residues 332-398), and identified a membrane-insertion domain (MID, residues 177-228) that facilitates acidic pH-dependent membrane insertion. In this manuscript, we further investigate structural determinants of cation channel formation by APOL1. Using a combination of site-directed mutagenesis and targeted chemical modification, our data indicates that the C-terminal heptad-repeat sequence (residues 368-395) is a bona fide leucine zipper domain (ZIP) that is required for cation channel formation as well as lysis of trypanosomes and mammalian cells. Using protein-wide cysteine-scanning mutagenesis, coupled with the substituted cysteine accessibility method (SCAM), we determined that in the open channel state both the N-terminal domain and the C-terminal ZIP domain are exposed on the intralumenal/extracellular side of the membrane and provide evidence that each APOL1 monomer contributes four transmembrane domains to the open cation channel conformation. Based on these data, we propose an oligomeric topology model in which the open APOL1 cation channel is assembled from the coiled-coil association of C-terminal ZIP domains.
Charles Schaub, Penny Lee, Alisha Racho-Jansen, Joe Giovinazzo, Nada Terra, Jayne Raper, Russell Thomson

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