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Jeffrey B. Kopp - One of the best experts on this subject based on the ideXlab platform.
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Lessons From APOL1 Animal Models
'Frontiers Media SA', 2021Co-Authors: Teruhiko Yoshida, Khun Zaw Latt, Jurgen Heymann, Jeffrey B. KoppAbstract:African-Americans have a three-fold higher rate of chronic kidney disease compared to European-Americans. Much of this excess risk is attributed to genetic variants in APOL1, encoding Apolipoprotein L1, that are present only in individuals with sub-Saharan ancestry. Although 10 years have passed since the discovery of APOL1 renal risk variants, the mechanisms by which APOL1 risk allele gene products damage glomerular cells remain incompletely understood. Many mechanisms have been reported in cell culture models, but few have been demonstrated to be active in transgenic models. In this narrative review, we will review existing APOL1 transgenic models, from flies to fish to mice; discuss findings and limitations from studies; and consider future research directions
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Apolipoprotein L1 testing in african americans involving the community in policy discussions
American Journal of Nephrology, 2019Co-Authors: Bessie A Young, Jeffrey B. Kopp, Barry I. Freedman, Erika Blacksher, Kerri L Cavanaugh, Stephanie M Fullerton, Ebele M Umeukeje, Kathleen M West, James G Wilson, Wylie BurkeAbstract:BACKGROUND Apolipoprotein A1 (APOL1) gene variants occurring in people of West African descent contribute to the greater burden of kidney disease among African Americans. These variants are associated with increased risk of nondiabetic nephropathy, more rapid progression of chronic kidney disease, and shorter survival of donor kidneys after transplantation. However, only a minority of people with APOL1-associated risk develops kidney disease and specific clinical measures to address APOL1-associated risk are lacking. Given these uncertainties, we sought to engage members of the African American public in discussions with other stakeholders about the appropriate use of APOL1 testing. METHODS Formative interviews with community members, researchers, and clinicians in Seattle WA, Nashville TN, and Jackson MS, provided baseline information about views toward APOL1 testing and informed the design of 3 community-based deliberations among African Americans. A national meeting held in March 2018 included 13 community members, 7 scientific advisors and 26 additional researchers, clinicians, bioethicists, patient advocates, and representatives from professional organizations and federal funding agencies. Using small break-out and plenary discussion, the group agreed on recommendations based on current knowledge about APOL1-associated risk. RESULTS Meeting outcomes included recommendations to develop educational materials about APOL1 for community members and clinicians; to offer APOL1 research results to participants; and on the use of APOL1testing in kidney transplant programs. The group recommended against the routine offer of APOL1 testing in clinical care. Areas of disagreement included whether kidney transplant programs should require APOL1 testing of prospective living donors or bar individuals with APOL1 risk from donating kidneys and whether testing should be available on request in routine clinical care. CONCLUSION We recommend continued discussion among stakeholders and concerted efforts to ensure active and informed participation of members of the affected community to guide research on APOL1 and kidney disease.
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apoL1 renal risk variants induce aberrant thp 1 monocyte differentiation and increase eicosanoid production via enhanced expression of cyclooxygenase 2
American Journal of Physiology-renal Physiology, 2018Co-Authors: Jung-hwa Ryu, Hila Roshanravan, Koji Okamoto, Hewang Lee, Ying Wang, Shashi Shrivastav, Jeffrey B. KoppAbstract:Apolipoprotein L1 (ApoL1) genetic variants are strongly associated with kidney diseases. We investigated the role of ApoL1 variants in monocyte differentiation and eicosanoid production in macropha...
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apoL1 renal risk variants induce aberrant thp 1 monocyte differentiation and increase eicosanoid production via enhanced expression of cyclooxygenase 2
American Journal of Physiology-renal Physiology, 2018Co-Authors: Jung-hwa Ryu, Hila Roshanravan, Koji Okamoto, Hewang Lee, Ying Wang, Shashi Shrivastav, Jeffrey B. KoppAbstract:Apolipoprotein L1 ( ApoL1) genetic variants are strongly associated with kidney diseases. 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 compared with control cells. ApoL1-G1 transfection induced additional CD206 and TGFB1 expression, and ApoL1-G2 transfection induced additional CD204 and TGFB1 expression. Gene expression of prostaglandin E2 (PGE2) synthase and thromboxane synthase and both gene and protein expression of cyclooxygenase-2 (COX-2) were increased by ApoL1-G1 and -G2 variants compared with -G0 transfection. Higher levels of PGE2 and thromboxane B2, a stable metabolite of thromboxane A2, and transforming growth factor (TGF)-β1 were released into the supernatant of cultured THP-1 cells transfected with ApoL1-G1 and -G2, but not -G0. The increase in PGE2, thromboxane B2, and TGF-β1 was inhibited by COX-2-specific inhibitor CAY10404 but not by COX-1-specific inhibitor SC-560. These results demonstrate a novel role of ApoL1 variants in the regulation of monocyte differentiation and eicosanoid metabolism, which could modify the immune response and promote inflammatory signaling within the local targeted organs and tissues including the kidney.
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apoL1 kidney disease risk variants an evolving landscape
Seminars in Nephrology, 2015Co-Authors: Patrick D Dummer, Sophie Limou, Avi Z Rosenberg, Jurgen A W Heymann, George E Nelson, Cheryl A Winkler, Jeffrey B. KoppAbstract:Apolipoprotein L1 (APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. Experimental evidence suggests a direct role of APOL1 in pore formation, cellular injury, and programmed cell death in renal injury. The APOL1 BH3 motif, often associated with cell death, is unlikely to play a role in APOL1-induced cytotoxicity because it is not conserved within the APOL family and is dispensable for cell death in vitro. We discuss two models for APOL1 trypanolytic activity: one involving lysosome permeabilization and another involving colloid-osmotic swelling of the cell body, as well as their relevance to human pathophysiology. Experimental evidence from human cell culture models suggests that both mechanisms may be operative. A systems biology approach whereby APOL1-associated perturbations in gene and protein expression in affected individuals are correlated with molecular pathways may be productive to elucidate APOL1 function in vivo.
Barry I. Freedman - One of the best experts on this subject based on the ideXlab platform.
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Apolipoprotein L1 testing in african americans involving the community in policy discussions
American Journal of Nephrology, 2019Co-Authors: Bessie A Young, Jeffrey B. Kopp, Barry I. Freedman, Erika Blacksher, Kerri L Cavanaugh, Stephanie M Fullerton, Ebele M Umeukeje, Kathleen M West, James G Wilson, Wylie BurkeAbstract:BACKGROUND Apolipoprotein A1 (APOL1) gene variants occurring in people of West African descent contribute to the greater burden of kidney disease among African Americans. These variants are associated with increased risk of nondiabetic nephropathy, more rapid progression of chronic kidney disease, and shorter survival of donor kidneys after transplantation. However, only a minority of people with APOL1-associated risk develops kidney disease and specific clinical measures to address APOL1-associated risk are lacking. Given these uncertainties, we sought to engage members of the African American public in discussions with other stakeholders about the appropriate use of APOL1 testing. METHODS Formative interviews with community members, researchers, and clinicians in Seattle WA, Nashville TN, and Jackson MS, provided baseline information about views toward APOL1 testing and informed the design of 3 community-based deliberations among African Americans. A national meeting held in March 2018 included 13 community members, 7 scientific advisors and 26 additional researchers, clinicians, bioethicists, patient advocates, and representatives from professional organizations and federal funding agencies. Using small break-out and plenary discussion, the group agreed on recommendations based on current knowledge about APOL1-associated risk. RESULTS Meeting outcomes included recommendations to develop educational materials about APOL1 for community members and clinicians; to offer APOL1 research results to participants; and on the use of APOL1testing in kidney transplant programs. The group recommended against the routine offer of APOL1 testing in clinical care. Areas of disagreement included whether kidney transplant programs should require APOL1 testing of prospective living donors or bar individuals with APOL1 risk from donating kidneys and whether testing should be available on request in routine clinical care. CONCLUSION We recommend continued discussion among stakeholders and concerted efforts to ensure active and informed participation of members of the affected community to guide research on APOL1 and kidney disease.
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effect of replacing race with Apolipoprotein L1 genotype in calculation of kidney donor risk index
American Journal of Transplantation, 2017Co-Authors: Bruce A Julian, Barry I. Freedman, Stephen O Pastan, Ajay K Israni, David P Schladt, Robert S Gaston, W M Brown, A Reevesdaniel, Sumit Mohan, Jasmin DiversAbstract:Renal allografts from deceased African American donors with two Apolipoprotein L1 gene (APOL1) renal-risk variants fail sooner than kidneys from donors with fewer variants. The Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied a 10-fold cross-validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross-validation was repeated 10 000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current-KDRI score for all donors was 1.4930 versus mean revised-KDRI score 1.2518 for 529 donors with no or one variant and 1.8527 for 93 donors with two variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence or absence of two APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85-90% of kidneys offered, and enhances the link between donor quality and recipient need.
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Mini-Review Gene–Gene and Gene–Environment Interactions
2016Co-Authors: In Apolipoprotein Gene-associated L Nephropathy, Barry I. Freedman, Karl SkoreckiAbstract:Molecular genetics have revolutionized the understanding of susceptibility to the broad spectrum of kidney diseases with light microscopic appearance of FSGS, particularly in populations with recent African ancestry. These disorders include idiopathic FSGS, HIV-associated nephropathy, severe lupus nephritis, sickle cell nephropathy, and the primary kidney disorder focal global glomerulosclerosis, which had historically been ascribed to systemic hypertension. FSGS was once thought to include a multitude of unrelated disorders with similar histologic appearance. However, variation in the Apolipoprotein L1 gene locus is now known to account for the vast majority of such cases in African Americans as well as nearly all the excess risk for FSGS and related forms of progressive nondiabetic nephropathy in populations with recent African ancestry, relative to European ancestry. Inheriting two coding Apolipoprotein L1 gene nephropathy risk variants is necessary for susceptibility to CKD; however, these variants alone are insufficient to produce disease. Thiswork reviews the evidence supporting second hits or modifying factors that affect risk for Apolipoprotein L1 gene-associated nephropathy and produce the protean manifestations of this common and complex syndrome. Targeting modifiable second factors will lead to preventive therapies for slowing progression of nondiabetic nephropathy in many patients possessing two Apolipoprotein L1 gene risk variants. This model of genetic risk coupled with modifiable second hits will serve as a paradigm applicable to patients with CKD of various etiologies as well as a host of other complex disorders
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APOL1 renal-risk variants associate with reduced cerebral white matter lesion volume and increased gray matter volume
Kidney international, 2016Co-Authors: Barry I. Freedman, Crystal A. Gadegbeku, R. Nick Bryan, Nicholette D. Palmer, Pamela J. Hicks, Michael V. Rocco, S. Carrie Smith, Christopher T. WhitlowAbstract:To assess Apolipoprotein L1 gene ( APOL1 ) renal-risk-variant effects on the brain, magnetic resonance imaging (MRI)-based cerebral volumes and cognitive function were assessed in 517 African American–Diabetes Heart Study (AA-DHS) Memory IN Diabetes (MIND) and 2568 hypertensive African American Systolic Blood Pressure Intervention Trial (SPRINT) participants without diabetes. Within these cohorts, 483 and 197 had cerebral MRI, respectively. AA-DHS participants were characterized as follows: 60.9% female, mean age of 58.6 years, diabetes duration 13.1 years, estimated glomerular filtration rate of 88.2 ml/min/1.73 m 2 , and a median spot urine albumin to creatinine ratio of 10.0 mg/g. In additive genetic models adjusting for age, sex, ancestry, scanner, intracranial volume, body mass index, hemoglobin A1c, statins, nephropathy, smoking, hypertension, and cardiovascular disease, APOL1 renal-risk-variants were positively associated with gray matter volume (β = 3.4 × 10 –3 ) and negatively associated with white matter lesion volume (β = –0.303) (an indicator of cerebral small vessel disease) and cerebrospinal fluid volume (β= –30707) (all significant), but not with white matter volume or cognitive function. Significant associations corresponding to adjusted effect sizes (β/SE) were observed with gray matter volume (0.16) and white matter lesion volume (–0.208), but not with cerebrospinal fluid volume (–0.251). Meta-analysis results with SPRINT Memory and Cognition in Decreased Hypertension (MIND) participants who had cerebral MRI were confirmatory. Thus, APOL1 renal-risk-variants are associated with larger gray matter volume and lower white matter lesion volume suggesting lower intracranial small vessel disease.
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association analysis of the cubilin cubn and megalin lrp2 genes with esrd in african americans
Clinical Journal of The American Society of Nephrology, 2016Co-Authors: Meijian Guan, Nicholette D. Palmer, Pamela J. Hicks, Donald W Bowden, Maggie C Y Ng, Barry I. FreedmanAbstract:Background and objectives Genetic variation in the cubilin (CUBN) gene is associated with albuminuria and CKD. Common and rare coding variants in CUBN and the gene encoding its transport partner megalin (LRP2) were assessed for association with ESRD in blacks. Design, setting, participants, & measurements Sixty-six CUBN and LRP2 single–nucleotide polymorphisms (SNPs) were selected and analyzed in this multistage study. Exome sequencing data from 529 blacks with type 2 diabetes (T2D) –associated ESRD and 535 controls lacking T2D or nephropathy (the Type 2 Diabetes Genes [T2D-GENES] Consortium) were first evaluated, focusing on coding variants in CUBN and LRP2; 15 potentially associated SNPs identified from the T2D-GENES Consortium as well as 51 other selected SNPs were then assessed in an independent T2D-ESRD sample set of blacks (the Affymetrix Axiom Biobank Genotyping Array [AXIOM]; 2041 patients with T2D-ESRD, 627 patients with T2D without nephropathy, and 1140 nondiabetic, non–nephropathy controls). A meta-analysis combining the T2D-GENES Consortium and the AXIOM data was performed for 18 overlapping SNPs. Additionally, all 66 SNPs were genotyped in the Wake Forest School of Medicine samples of blacks with nondiabetic ESRD (885 patients with nondiabetic ESRD and 721 controls). Association testing with ESRD was performed in models including age, sex, African ancestry proportion, and Apolipoprotein L1 gene renal-risk variants. Results CUBN SNP rs1801239 (I2984V), previously associated with albuminuria, was significantly associated with T2D-ESRD in blacks (the T2D-GENES Consortium and the AXIOM meta-analysis, P=0.03; odds ratio, 1.31; 95% confidence interval, 1.03 to 1.67; minor allele frequency =0.028). A novel LRP2 missense variant, rs17848169 (N2632D), was also significantly protective from T2D-ESRD (the T2D-GENES Consortium and the AXIOM, P Conclusions Evidence for genetic association exists between a cubilin and a rare megalin variant with diabetes-associated ESRD in populations with recent African ancestry.
Carl D Langefeld - One of the best experts on this subject based on the ideXlab platform.
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genome wide association studies suggest that apoL1 environment interactions more likely trigger kidney disease in african americans with nondiabetic nephropathy than strong apoL1 second gene interactions
Kidney International, 2018Co-Authors: Carl D Langefeld, Bruce A Julian, Mary E Comeau, Jennifer A Croker, Meijian Guan, Latchezar Dimitrov, Poorva Mudgal, Mitzie Spainhour, Jeffrey C Edberg, Jasmin DiversAbstract:African Americans carrying two Apolipoprotein L1 gene (APOL1) renal risk variants have a high risk for nephropathy. However, only a minority develops end-stage renal disease (ESRD). Hence, modifying factors likely contribute to initiation of kidney disease such as endogenous (HIV infection) or exogenous (interferon treatment) environmental modifiers. In this report, genome-wide association studies and a meta-analysis were performed to identify novel loci for nondiabetic ESRD in African Americans and to detect genetic modifiers in APOL1-associated nephropathy. Two African American cohorts were analyzed, 1749 nondiabetic ESRD cases and 1136 controls from Wake Forest and 901 lupus nephritis (LN)–ESRD cases and 520 controls with systemic lupus erythematosus but lacking nephropathy from the LN-ESRD Consortium. Association analyses adjusting for APOL1 G1/G2 renal-risk variants were completed and stratified by APOL1 risk genotype status. Individual genome-wide association studies and meta-analysis results of all 2650 ESRD cases and 1656 controls did not detect significant genome-wide associations with ESRD beyond APOL1. Similarly, no single nucleotide polymorphism showed significant genome-wide evidence of an interaction with APOL1 risk variants. Thus, although variants with small individual effects cannot be ruled out and are likely to exist, our results suggest that APOL1-environment interactions may be of greater clinical importance in triggering nephropathy in African Americans than APOL1 interactions with other single nucleotide polymorphisms.
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Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the systolic blood pressure intervention trial
Kidney International, 2015Co-Authors: Carl D Langefeld, Jasmin Divers, Nicholas M Pajewski, Amret T Hawfield, David M Reboussin, Diane E Bild, George A Kaysen, Paul L Kimmel, Dominic S Raj, Ana C RicardoAbstract:Apolipoprotein L1 gene ( APOL1 ) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans (AAs). Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2571 AAs from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary, or carotid artery revascularization) and CKD (eGFR under 60ml/min per 1.73m 2 and/or UACR over 30mg/g). AA SPRINT participants were 45.3% female with a mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100)mmHg, eGFR 76.3 (77.1) ml/min per 1.73m 2 , and UACR 49.9 (9.2)mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08–1.73) and log UACR estimated slope ( β ) 0.33) and negatively associated with eGFR ( β -3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82–1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not with prevalent CVD in AAs with a UACR under 1000mg/g.
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end stage renal disease in african americans with lupus nephritis is associated with apoL1
Arthritis & Rheumatism, 2014Co-Authors: Barry I. Freedman, Carl D Langefeld, Pamela J. Hicks, Kelly K Andringa, Jennifer A Croker, Adrienne H Williams, Neva E Garner, Daniel J Birmingham, Lee A Hebert, Mark S SegalAbstract:Objective Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the Apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.
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Apolipoprotein L1 gene variants associate with hypertension attributed nephropathy and the rate of kidney function decline in african americans
Kidney International, 2013Co-Authors: Michael S Lipkowitz, Carl D Langefeld, Barry I. Freedman, Donald W Bowden, Mary E Comeau, W Linda H Kao, Brad C Astor, Erwin P Bottinger, Sudha K Iyengar, Paul E KlotmanAbstract:Despite intensive antihypertensive therapy there was a high incidence of renal end points in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. To better understand this, coding variants in the Apolipoprotein L1 ( APOL1 ) and the nonmuscle myosin heavy chain 9 ( MYH9 ) genes were evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a case–control study. Clinical data and DNA were available for 675 AASK participant cases and 618 African American non-nephropathy control individuals. APOL1 G1 and G2, and MYH9 E1 variants along with 44 ancestry informative markers, were genotyped with allele frequency differences between cases and controls analyzed by logistic regression multivariable models adjusting for ancestry, age, and gender. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, such as a baseline urine protein to creatinine ratio over 0.6g/g or a serum creatinine over 3mg/dl during follow-up, the association was strengthened with odds ratios of 6.29 and 4.61, respectively. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. Thus, kidney disease in AASK participants was strongly associated with APOL1 renal risk variants.
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sickle cell trait is not independently associated with susceptibility to end stage renal disease in african americans
Kidney International, 2011Co-Authors: Pamela J. Hicks, Carl D Langefeld, Jasmin Divers, Anthony J. Bleyer, Vimal K Derebail, Patrick H Nachman, Donald W Bowden, Barry I. FreedmanAbstract:Conflicting reports exist as to whether sickle cell trait is a risk factor for the progression of nephropathy. In order to determine whether African Americans with sickle cell trait are at increased risk for kidney disease, we assessed the genetic association between sickle cell trait and end-stage renal disease (ESRD). Hemoglobin S, non-muscle myosin heavy chain 9 ( MYH9 ), and Apolipoprotein L1 ( APOL1 ) risk variants were genotyped in 3258 unrelated African Americans: 1085 with non-diabetic ESRD, 996 with type 2 diabetes-associated ESRD, and 1177 controls. Since APOL1 is strongly associated with ESRD in African Americans, interactions between APOL1 and MYH9 risk variants and hemoglobin S were assessed using case-only and case-control centered two-way logistic regression interaction analyses. The sickle cell trait genotype frequencies were 8.7% in non-diabetic ESRD, 7.1% in type 2 diabetes-ESRD, and 7.2% in controls. There was no age-, gender-, and admixture-adjusted significance for sickle cell trait association with non-diabetic ESRD (odds ratio 1.16); type 2 diabetes-ESRD (odds ratio 1.01); or all-cause ESRD (combined non-diabetic and type 2 diabetic-ESRD patients compared to the controls; odds ratio 1.05) in dominant models. In addition, no evidence of APOL1 or MYH9 interactions with sickle cell trait was detected. Hence, sickle cell trait is not associated with diabetic or non-diabetic ESRD in a large sample of African Americans.
Hewang Lee - One of the best experts on this subject based on the ideXlab platform.
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apoL1 renal risk variants induce aberrant thp 1 monocyte differentiation and increase eicosanoid production via enhanced expression of cyclooxygenase 2
American Journal of Physiology-renal Physiology, 2018Co-Authors: Jung-hwa Ryu, Hila Roshanravan, Koji Okamoto, Hewang Lee, Ying Wang, Shashi Shrivastav, Jeffrey B. KoppAbstract:Apolipoprotein L1 (ApoL1) genetic variants are strongly associated with kidney diseases. We investigated the role of ApoL1 variants in monocyte differentiation and eicosanoid production in macropha...
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apoL1 renal risk variants induce aberrant thp 1 monocyte differentiation and increase eicosanoid production via enhanced expression of cyclooxygenase 2
American Journal of Physiology-renal Physiology, 2018Co-Authors: Jung-hwa Ryu, Hila Roshanravan, Koji Okamoto, Hewang Lee, Ying Wang, Shashi Shrivastav, Jeffrey B. KoppAbstract:Apolipoprotein L1 ( ApoL1) genetic variants are strongly associated with kidney diseases. 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 compared with control cells. ApoL1-G1 transfection induced additional CD206 and TGFB1 expression, and ApoL1-G2 transfection induced additional CD204 and TGFB1 expression. Gene expression of prostaglandin E2 (PGE2) synthase and thromboxane synthase and both gene and protein expression of cyclooxygenase-2 (COX-2) were increased by ApoL1-G1 and -G2 variants compared with -G0 transfection. Higher levels of PGE2 and thromboxane B2, a stable metabolite of thromboxane A2, and transforming growth factor (TGF)-β1 were released into the supernatant of cultured THP-1 cells transfected with ApoL1-G1 and -G2, but not -G0. The increase in PGE2, thromboxane B2, and TGF-β1 was inhibited by COX-2-specific inhibitor CAY10404 but not by COX-1-specific inhibitor SC-560. These results demonstrate a novel role of ApoL1 variants in the regulation of monocyte differentiation and eicosanoid metabolism, which could modify the immune response and promote inflammatory signaling within the local targeted organs and tissues including the kidney.
Jasmin Divers - One of the best experts on this subject based on the ideXlab platform.
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Apolipoprotein L1 risk genotypes in Ghanaian patients with systemic lupus erythematosus: a prospective cohort study
'BMJ', 2021Co-Authors: Ashira Blazer, Ida Dzifa Dey, Janet Nwaukoni, Margaret Reynolds, Festus Ankrah, Huda Algasas, Tasneem Ahmed, Jasmin DiversAbstract:Objective Two Apolipoprotein L1 (APOL1) risk variants (RV) are enriched in sub-Saharan African populations due to conferred resistance to Trypanosoma brucei. These variants associate with adverse renal outcomes by multiple causes including SLE. Despite emerging reports that SLE is common in Ghana, where APOL1 variant allelic frequencies are high, the regional contribution to SLE outcomes has not been described. Accordingly, this prospective longitudinal cohort study tested the associations between APOL1 high-risk genotypes and kidney outcomes, organ damage accrual and death in 100 Ghanaian patients with SLE.Methods This was a prospective cohort study of 100 SLE outpatients who sought care at Korle bu Teaching Hospital in Accra, Ghana. Adult patients who met 4 American College of Rheumatology criteria for SLE were genotyped for APOL1 and followed longitudinally for SLE activity as measured by the Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) hybrid and organ injury as measured by the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at baseline and every 6 months for 1 year. Outcomes of interest were kidney function, SDI and case fatality.Results Assuming a recessive inheritance, the APOL1 high-risk genotype (2RV) associated with end-stage renal disease (ESRD) at an OR of 14 (p=0.008). These patients accrued more SDI points particularly in renal and neurological domains. The SDI was 81.3% higher in 2RV patients compared with 0RV or 1RV patients despite no difference in SLE activity (p=0.01). After a 12-month period of observation, 3/12 (25%) of the 2RV patients died compared with 2/88 (2.3%) of the 0RV or 1RV carriers (OR=13.6, p=0.01). Deaths were due to end-stage kidney disease and heart failure.Conclusion APOL1 RVs were heritable risk factors for morbidity and mortality in this Ghanaian SLE cohort. Despite no appreciable differences in SLE activity, APOL1 high-risk patients exhibited progressive renal disease, organ damage accrual and a 13-fold higher case fatality
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genome wide association studies suggest that apoL1 environment interactions more likely trigger kidney disease in african americans with nondiabetic nephropathy than strong apoL1 second gene interactions
Kidney International, 2018Co-Authors: Carl D Langefeld, Bruce A Julian, Mary E Comeau, Jennifer A Croker, Meijian Guan, Latchezar Dimitrov, Poorva Mudgal, Mitzie Spainhour, Jeffrey C Edberg, Jasmin DiversAbstract:African Americans carrying two Apolipoprotein L1 gene (APOL1) renal risk variants have a high risk for nephropathy. However, only a minority develops end-stage renal disease (ESRD). Hence, modifying factors likely contribute to initiation of kidney disease such as endogenous (HIV infection) or exogenous (interferon treatment) environmental modifiers. In this report, genome-wide association studies and a meta-analysis were performed to identify novel loci for nondiabetic ESRD in African Americans and to detect genetic modifiers in APOL1-associated nephropathy. Two African American cohorts were analyzed, 1749 nondiabetic ESRD cases and 1136 controls from Wake Forest and 901 lupus nephritis (LN)–ESRD cases and 520 controls with systemic lupus erythematosus but lacking nephropathy from the LN-ESRD Consortium. Association analyses adjusting for APOL1 G1/G2 renal-risk variants were completed and stratified by APOL1 risk genotype status. Individual genome-wide association studies and meta-analysis results of all 2650 ESRD cases and 1656 controls did not detect significant genome-wide associations with ESRD beyond APOL1. Similarly, no single nucleotide polymorphism showed significant genome-wide evidence of an interaction with APOL1 risk variants. Thus, although variants with small individual effects cannot be ruled out and are likely to exist, our results suggest that APOL1-environment interactions may be of greater clinical importance in triggering nephropathy in African Americans than APOL1 interactions with other single nucleotide polymorphisms.
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effect of replacing race with Apolipoprotein L1 genotype in calculation of kidney donor risk index
American Journal of Transplantation, 2017Co-Authors: Bruce A Julian, Barry I. Freedman, Stephen O Pastan, Ajay K Israni, David P Schladt, Robert S Gaston, W M Brown, A Reevesdaniel, Sumit Mohan, Jasmin DiversAbstract:Renal allografts from deceased African American donors with two Apolipoprotein L1 gene (APOL1) renal-risk variants fail sooner than kidneys from donors with fewer variants. The Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied a 10-fold cross-validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross-validation was repeated 10 000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current-KDRI score for all donors was 1.4930 versus mean revised-KDRI score 1.2518 for 529 donors with no or one variant and 1.8527 for 93 donors with two variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence or absence of two APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85-90% of kidneys offered, and enhances the link between donor quality and recipient need.
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Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the systolic blood pressure intervention trial
Kidney International, 2015Co-Authors: Carl D Langefeld, Jasmin Divers, Nicholas M Pajewski, Amret T Hawfield, David M Reboussin, Diane E Bild, George A Kaysen, Paul L Kimmel, Dominic S Raj, Ana C RicardoAbstract:Apolipoprotein L1 gene ( APOL1 ) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans (AAs). Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2571 AAs from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary, or carotid artery revascularization) and CKD (eGFR under 60ml/min per 1.73m 2 and/or UACR over 30mg/g). AA SPRINT participants were 45.3% female with a mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100)mmHg, eGFR 76.3 (77.1) ml/min per 1.73m 2 , and UACR 49.9 (9.2)mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08–1.73) and log UACR estimated slope ( β ) 0.33) and negatively associated with eGFR ( β -3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82–1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not with prevalent CVD in AAs with a UACR under 1000mg/g.
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sickle cell trait is not independently associated with susceptibility to end stage renal disease in african americans
Kidney International, 2011Co-Authors: Pamela J. Hicks, Carl D Langefeld, Jasmin Divers, Anthony J. Bleyer, Vimal K Derebail, Patrick H Nachman, Donald W Bowden, Barry I. FreedmanAbstract:Conflicting reports exist as to whether sickle cell trait is a risk factor for the progression of nephropathy. In order to determine whether African Americans with sickle cell trait are at increased risk for kidney disease, we assessed the genetic association between sickle cell trait and end-stage renal disease (ESRD). Hemoglobin S, non-muscle myosin heavy chain 9 ( MYH9 ), and Apolipoprotein L1 ( APOL1 ) risk variants were genotyped in 3258 unrelated African Americans: 1085 with non-diabetic ESRD, 996 with type 2 diabetes-associated ESRD, and 1177 controls. Since APOL1 is strongly associated with ESRD in African Americans, interactions between APOL1 and MYH9 risk variants and hemoglobin S were assessed using case-only and case-control centered two-way logistic regression interaction analyses. The sickle cell trait genotype frequencies were 8.7% in non-diabetic ESRD, 7.1% in type 2 diabetes-ESRD, and 7.2% in controls. There was no age-, gender-, and admixture-adjusted significance for sickle cell trait association with non-diabetic ESRD (odds ratio 1.16); type 2 diabetes-ESRD (odds ratio 1.01); or all-cause ESRD (combined non-diabetic and type 2 diabetic-ESRD patients compared to the controls; odds ratio 1.05) in dominant models. In addition, no evidence of APOL1 or MYH9 interactions with sickle cell trait was detected. Hence, sickle cell trait is not associated with diabetic or non-diabetic ESRD in a large sample of African Americans.