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Jia-Yue Zhang, Minxian Wang, Lei Tian, Giulio Genovese, Paul Yan, James G Wilson, Ravi Thadhani, Amy K Mottl, Gerald B Appel, Alexander G Bick, Matthew G Sampson, Seth L Alper, David J Friedman, Martin R Pollak
People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1 We performed an admixture mapping study to identify genetic modifiers of APOL1 -associated kidney disease...
March 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Barry I Freedman, Bruce A Julian
No abstract text is available yet for this article.
March 9, 2018: Journal of the American Society of Nephrology: JASN
Magambo Phillip Kimuda, Harry Noyes, Julius Mulindwa, John Enyaru, Vincent Pius Alibu, Issa Sidibe, Dieuodonne Mumba Ngoyi, Christiane Hertz-Fowler, Annette MacLeod, Özlem Tastan Bishop, Enock Matovu
BACKGROUND: Human African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT...
February 22, 2018: PLoS Neglected Tropical Diseases
Barry I Freedman, Amy L Kistler, Peter Skewes-Cox, Don Ganem, Mitzie Spainhour, Jolyn Turner, Jasmin Divers, Carl D Langefeld, Mariana Murea, Pamela J Hicks, Ashok K Hemal, James A Snipes, Lihong Zhao, Johanna R Abend, Douglas S Lyles, Lijun Ma, Karl L Skorecki
Background: Viral infections can trigger chronic kidney disease (CKD) and the urine virome may inform risk. The Natural History of APOL1-Associated Nephropathy Study (NHAANS) reported that urine JC polyomavirus (JCPyV) associated with a lower risk of APOL1-associated nephropathy in African Americans. Herein, association was assessed between urine JCPyV with CKD in African Americans independent from the APOL1 genotype. Methods: Quantitative polymerase chain reaction was performed for urinary detection of JCPyV and BK polyoma virus (BKPyV) in 200 newly recruited nondiabetic African Americans...
February 6, 2018: Nephrology, Dialysis, Transplantation
Kimberly J Reidy, Rebecca Hjorten, Rulan S Parekh
PURPOSE OF REVIEW: Understanding the genetic risk of APOL1 in children and young adults is important given the lifetime risk of hypertension and kidney disease among children of African descent. We review recent epidemiologic and biologic findings on the effects of APOL1 and kidney disease. RECENT FINDINGS: APOL1 in children and young adults is associated with hypertension, albuminuria and more rapid decline in kidney function and progression to end-stage kidney disease, especially among those with glomerular causes of kidney disease, and those affected by sickle cell disease or HIV...
February 5, 2018: Current Opinion in Pediatrics
Zhen Wang, Li-Min Guo, Hong-Kang Zhou, Hong-Ke Qu, Shu-Chao Wang, Feng-Xia Liu, Dan Chen, Ju-Fang Huang, Kun Xiong
Evolutionary medicine has proven helpful to understand the origin of human disease, e.g. in identifying causal roles of recent environmental changes impacting on human physiology (environment-phenotype mismatch). In contrast, diseases affecting only a limited number of members of a species often originate from evolutionary trade-offs for usually physiologic adaptations assuring reproductive success in the context of extrinsic threats. For example, the G1 and G2 variants of the APOL1 gene supporting control of Trypanosoma infection come with the trade-off that they promote the progression of kidney disease...
February 1, 2018: Histology and Histopathology
Jeffrey B Kopp, Hila Roshanravan, Koji Okamoto
PURPOSE OF REVIEW: To review publications relating to apolipoprotein L1 (APOL1) renal risk variants published 2017. RECENT FINDINGS: The study of APOL1 variants continues to be highly active; 24 articles published in 2017 were selected to highlight. These include clinical studies of kidney disease, kidney transplantation, hypertension, cardiovascular disease, and genetic diversity. Laboratory studies included APOL1 association with vesicle-associated membrane soluble N-ethylmaleimide-sensitive factor activating protein receptor protein and with soluble urokinase-type plasminogen activator receptor, mitochondrial dysfunction, endolysosomal dysfunction, and inflammasome activation...
January 30, 2018: Current Opinion in Nephrology and Hypertension
Sebastian Zoll, Harriet Lane-Serff, Shahid Mehmood, Jonathan Schneider, Carol V Robinson, Mark Carrington, Matthew K Higgins
Only two trypanosome subspecies are able to cause human African trypanosomiasis. To establish an infection in human blood, they must overcome the innate immune system by resisting the toxic effects of trypanolytic factor 1 and trypanolytic factor 2 (refs. 1,2). These lipoprotein complexes contain an active, pore-forming component, apolipoprotein L1 (ApoL1), that causes trypanosome cell death 3 . One of the two human-infective subspecies, Trypanosoma brucei rhodesiense, differs from non-infective trypanosomes solely by the presence of the serum resistance-associated protein, which binds directly to ApoL1 and blocks its pore-forming capacity3-5...
January 22, 2018: Nature Microbiology
Abheepsa Mishra, Kamesh Ayasolla, Vinod Kumar, Xiqian Lan, Himanshu Vashistha, Rukhsana Aslam, Ali Hussain, Sheetal Chowdhary, Shadafarin Marashi Shoshtari, Nitpriya Paliwal, Waldemar Popik, Moin A Saleem, Ashwani Malhotra, Leonard G Meggs, Karl Skorecki, Pravin C Singhal
The loss of podocyte (PD) molecular phenotype is an important feature of diabetic podocytopathy. We hypothesized that high glucose (HG) induces dedifferentiation in differentiated podocytes (DPD) through alterations in APOL1-microRNA (miR) 193a axis. HG-induced DPDs dedifferentiation manifested in the form of down regulation of WT1 and upregulation of PAX2 expression. WT1- silenced DPDs displayed enhanced expression of PAX2. Immunoprecipitation (IP) of DPD cellular lysates with anti-WT1 antibody revealed formation of WT1 repressor complexes containing Polycomb group proteins (PcG), EZH2, Menin, and DNA methyl transferase (DNMT1), whereas, silencing of either WT1 or DNMT1 disrupted this complex with enhanced expression of PAX2...
January 10, 2018: American Journal of Physiology. Renal Physiology
Hewang Lee, Hila Roshanravan, Ying Wang, Koji Okamoto, Junghwa Ryu, Shashi Shrivastav, Peng Qu, Jeffrey B Kopp, Jeffrey B Kopp
Apolipoprotein L1 (APOL1) genetic variants are strongly associated with kidney disease. We investigated the role of APOL1 variants in monocyte differentiation and eicosanoid production in macrophages, as activated tissue macrophages in kidney might contribute to kidney injury. In human monocyte THP-1 cells, transient overexpression of APOL1 (G0, G1, G2) by transfection resulted in a 5 to 11-fold increase in CD14 and CD68 gene expression, similar to that seen with phorbol-12-myristate acetate treatment. All APOL1 variants caused monocytes to differentiate into atypical M1 macrophages with marked increase in M1 markers CD80, TNF, IL1B, and IL6 and modest increase in the M2 marker CD163 as compared to control cells...
January 10, 2018: American Journal of Physiology. Renal Physiology
Monika Bhardwaj, Souren Paul, Rekha Jakhar, Imran Khan, Ji In Kang, Ho Min Kim, Jong Won Yun, Seon-Jin Lee, Hee Jun Cho, Hee Gu Lee, Sun Chul Kang
Heat shock transcription factor-1 (HSF-1) guards the cancerous cells proteome against the alterations in protein homeostasis generated by their hostile tumor microenvironment. Contrasting with the classical induction of heat shock proteins, the pro-oncogenic activities of HSF-1 remains to be explored. Therefore, cancer's fragile proteostatic pathway governed by HSF-1 could be a potential therapeutic target and novel biomarker by natural compounds. Vitexin, a natural flavonoid has been documented as a potent anti-tumor agent on various cell lines...
December 22, 2017: Oncotarget
Rachel B Currier, Anneli Cooper, Hollie Burrell-Saward, Annette MacLeod, Sam Alsford
In contrast to Trypanosoma brucei gambiense and T. b. rhodesiense (the causative agents of human African trypanosomiasis), T. b. brucei is lysed by apolipoprotein-L1 (apoL1)-containing human serum trypanolytic factors (TLF), rendering it non-infectious to humans. While the mechanisms of TLF1 uptake, apoL1 membrane integration, and T. b. gambiense and T. b. rhodesiense apoL1-resistance have been extensively characterised, our understanding of the range of factors that drive apoL1 action in T. b. brucei is limited...
January 18, 2018: PLoS Pathogens
Michael D Hughson, Wendy E Hoy, Susan A Mott, John F Bertram, Cheryl A Winkler, Jeffrey B Kopp
Introduction: The relationship of APOL1 renal risk variants to cardiovascular disease (CVD) is controversial and was the subject of this investigation. Methods: Age, cause of death, and nephrosclerosis (the latter defined by glomerulosclerosis) were analyzed in the autopsies of 162 African Americans and 136 whites genotyped for APOL1 risk alleles. Results: Sudden deaths represented >75% of CVD autopsies for both races and all-risk genotypes...
January 2018: KI Reports
Mona D Doshi, Mariella Ortigosa-Goggins, Amit X Garg, Lihua Li, Emilio D Poggio, Cheryl A Winkler, Jeffrey B Kopp
Black living kidney donors are at higher risk of developing kidney disease than white donors. We examined the effect of the APOL1 high-risk genotype on postdonation renal function in black living kidney donors and evaluated whether this genotype alters the association between donation and donor outcome. We grouped 136 black living kidney donors as APOL1 high-risk (two risk alleles; n =19; 14%) or low-risk (one or zero risk alleles; n =117; 86%) genotype. Predonation characteristics were similar between groups, except for lower mean±SD baseline eGFR (CKD-EPI equation) in donors with the APOL1 high-risk genotype (98±17 versus 108±20 ml/min per 1...
January 16, 2018: Journal of the American Society of Nephrology: JASN
Adebowale Adeyemo, Christopher Esezobor, Adaobi Solarin, Asiri Abeyagunawardena, Jameela A Kari, Sherif El Desoky, Larry A Greenbaum, Margret Kamel, Mahmoud Kallash, Cynthia Silva, Alex Young, Tracey E Hunley, Nilka de Jesus-Gonzalez, Tarak Srivastava, Rasheed Gbadegesin
BACKGROUND: Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1 and APOL1 variants as risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1 association. STUDY DESIGN: Case-control study. SETTING & PARTICIPANTS: African American children with SSNS or steroid-resistant nephrotic syndrome (SRNS) were enrolled from Duke University and centers participating in the Midwest Pediatric Nephrology Consortium...
December 22, 2017: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
Ambroise Wonkam, Khuthala Mnika, Valentina J Ngo Bitoungui, Bernard Chetcha Chemegni, Emile R Chimusa, Collet Dandara, Andre P Kengne
We aimed to investigate the clinical and genetic predictors of painful vaso-occlusive crises (VOC) in sickle cell disease (SCD) in Cameroon. Socio-demographics, clinical variables/events and haematological indices were acquired. Genotyping was performed for 40 variants in 17 pain-related genes, three fetal haemoglobin (HbF)-promoting loci, two kidney dysfunctions-related genes, and HBA1/HBA2 genes. Statistical models using regression frameworks were performed in R® . A total of 436 hydoxycarbamide- and opioid-naïve patients were studied; median age was 16 years...
January 2018: British Journal of Haematology
John F O'Toole, William Schilling, Diana Kunze, Sethu M Madhavan, Martha Konieczkowski, Yaping Gu, Liping Luo, Zhenzhen Wu, Leslie A Bruggeman, John R Sedor
Coding variants in the APOL1 gene are associated with kidney diseases in African ancestral populations; yet, the underlying biologic mechanisms remain uncertain. Variant-dependent autophagic and cytotoxic cell death have been proposed as pathogenic pathways mediating kidney injury. To examine this possibility, we conditionally expressed APOL1-G0 (reference), -G1, and -G2 (variants) using a tetracycline-regulated system in HEK293 cells. Autophagy was monitored biochemically and cell death was measured using multiple assays...
March 2018: Journal of the American Society of Nephrology: JASN
Joseph V Nally
Recent decades have seen great advances in the understanding of chronic kidney disease, spurred by standardizing disease definitions and large-scale patient surveillance. African Americans are disproportionately affected by the disease, and recently discovered genetic variants in APOL1 that protect against sleeping sickness in Africa provide an important explanation for the increased burden. Studies are now under way to determine if genetic testing of African American transplant donors and recipients is advisable...
November 2017: Cleveland Clinic Journal of Medicine
Inna Mohamadou, Alexandre Hertig
No abstract text is available yet for this article.
December 2017: Néphrologie & Thérapeutique
William S Oetting, Casey Dorr, Rory P Remmel, Arthur J Matas, Ajay K Israni, Pamala A Jacobson
Purpose of review: Identification of genetic variants to aid in individualized treatment of solid organ allograft recipients would improve graft survival. We will review the current state of knowledge for associations of variants with transplant outcomes. Recent findings: Many studies have yet to exhibit robust and reproducible results, however, pharmacogenomic studies focusing on cytochrome P450 (CYP) enzymes, transporters and HLA variants have shown strong associations with outcomes and have relevance towards drugs used in transplant...
June 2017: Current Transplantation Reports
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