scholarly journals Variation inAPOL1Contributes to Ancestry-Level Differences in HDLc-Kidney Function Association

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Amy Rebecca Bentley ◽  
Ayo P. Doumatey ◽  
Guanjie Chen ◽  
Hanxia Huang ◽  
Jie Zhou ◽  
...  
Keyword(s):  
African Americans ◽  
Kidney Disease ◽  
Disease Risk ◽  
African Ancestry ◽  
Gene Encoding ◽  
Risk Variant ◽  
European Americans ◽  
Nationally Representative ◽  
High Density Cholesterol

Low levels of high-density cholesterol (HDLc) accompany chronic kidney disease, but the association between HDLc and the estimated glomerular filtration rate (eGFR) in the general population is unclear. We investigated the HDLc-eGFR association in nondiabetic Han Chinese (HC,n=1100), West Africans (WA,n=1497), and African Americans (AA,n=1539). There were significant differences by ancestry: HDLc was positively associated with eGFR in HC (β=0.13,P<0.0001), but negatively associated among African ancestry populations (WA: −0.19,P<0.0001; AA: −0.09,P=0.02). These differences were also seen in nationally-representative NHANES data (among European Americans: 0.09,P=0.005; among African Americans −0.14,P=0.03). To further explore the findings in African ancestry populations, we investigated the role of an African ancestry-specific nephropathy risk variant, rs73885319, in the gene encoding HDL-associated APOL1. Among AA, an inverse HDLc-eGFR association was observed only with the risk genotype (−0.38 versus 0.001;P=0.03). This interaction was not seen in WA. In summary, counter to expectation, an inverse HDLc-eGFR association was observed among those of African ancestry. Given theAPOL1× HDLc interaction among AA, genetic factors may contribute to this paradoxical association. Notably, these findings suggest that the unexplained mechanism by whichAPOL1affects kidney-disease risk may involve HDLc.

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

2021 ◽  
Vol 14 (8) ◽  
Author(s):  
Gizelle M. McCarthy ◽  
Angelo Blasio ◽  
Olivia G. Donovan ◽  
Lena B. Schaller ◽  
Althea Bock-Hughes ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Disease Risk ◽  
Large Fraction ◽  
African Ancestry ◽  
Kidney Injury ◽  
Artificial Chromosome ◽  
Gain Of Function ◽  
Risk Variant ◽  
Protein Levels ◽  
Ifn Γ

ABSTRACT 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.

scholarly journals APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases

2015 ◽  
Vol 113 (4) ◽  
pp. 830-837 ◽  
Author(s):  
Opeyemi A. Olabisi ◽  
Jia-Yue Zhang ◽  
Lynn VerPlank ◽  
Nathan Zahler ◽  
Salvatore DiBartolo ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Protein Kinases ◽  
Intracellular Signaling ◽  
Cultured Cells ◽  
Disease Risk ◽  
African Ancestry ◽  
High Rate ◽  
Cell Swelling ◽  
Risk Variant ◽  
Risk Variants

Two specific genetic variants of the apolipoprotein L1 (APOL1) gene are responsible for the high rate of kidney disease in people of recent African ancestry. Expression in cultured cells of these APOL1 risk variants, commonly referred to as G1 and G2, results in significant cytotoxicity. The underlying mechanism of this cytotoxicity is poorly understood. We hypothesized that this cytotoxicity is mediated by APOL1 risk variant-induced dysregulation of intracellular signaling relevant for cell survival. To test this hypothesis, we conditionally expressed WT human APOL1 (G0), the APOL1 G1 variant, or the APOL1 G2 variant in human embryonic kidney cells (T-REx-293) using a tetracycline-mediated (Tet-On) system. We found that expression of either G1 or G2 APOL1 variants increased apparent cell swelling and cell death compared with G0-expressing cells. These manifestations of cytotoxicity were preceded by G1 or G2 APOL1-induced net efflux of intracellular potassium as measured by X-ray fluorescence, resulting in the activation of stress-activated protein kinases (SAPKs), p38 MAPK, and JNK. Prevention of net K+ efflux inhibited activation of these SAPKs by APOL1 G1 or G2. Furthermore, inhibition of SAPK signaling and inhibition of net K+ efflux abrogated cytotoxicity associated with expression of APOL1 risk variants. These findings in cell culture raise the possibility that nephrotoxicity of APOL1 risk variants may be mediated by APOL1 risk variant-induced net loss of intracellular K+ and subsequent induction of stress-activated protein kinase pathways.

scholarly journals The Effect of Biracial Status and Color on Crystallized Intelligence in the U.S.-Born African–European American Population

Psych ◽  
2019 ◽  
Vol 1 (1) ◽  
pp. 44-54
Author(s):  
John Fuerst ◽  
Richard Lynn ◽  
Emil Kirkegaard
Keyword(s):  
African Americans ◽  
Cognitive Ability ◽  
African Ancestry ◽  
Significant Negative Correlation ◽  
European Ancestry ◽  
European American ◽  
Crystallized Intelligence ◽  
Black And White ◽  
Nationally Representative ◽  
Sub Saharan

The relationship between biracial status, color, and crystallized intelligence was examined in a nationally representative sample of adult Black and White Americans. First, it was found that self-identifying biracial individuals, who were found to be intermediate in color and in self-reported ancestry, had intermediate levels of crystallized intelligence relative to self-identifying White (mostly European ancestry) and Black (mostly sub-Saharan African ancestry) Americans. The results were transformed to an IQ scale: White (M = 100.00, N = 7569), primarily White–biracial (M = 96.07, N = 43, primarily Black–biracial (M = 94.14 N = 50), and Black (M = 89.81, N = 1381). Next, among self-identifying African Americans, a statistically significant negative correlation of r = −0.102 (N = 637) was found between interviewer-rated darker facial color and vocabulary scores. After correction for the reliability of the measures, this correlation increased to r = −0.21. Corrections for the validity of color as an index of African ancestry would raise this correlation to around r = −0.48. This association among self-identifying African Americans was not accounted for by confounding factors, such as region of residence and interviewer race, or by parental socioeconomic status and individual educational attainment. In the multivariate models, the standardized betas for color and crystallized intelligence among African Americans ranged from β = −0.112 to β = −0.142. Based on the coefficients from the multivariate analysis, it was further found that cognitive ability was a significant mediator in the context of color and education, while education was not in the context of color and cognitive ability. It is concluded that these results further substantiate the statistical relation between intelligence and biogeographic ancestry in African and European American populations.

scholarly journals Maternal obesity increases the risk of metabolic disease and impacts renal health in offspring

2018 ◽  
Vol 38 (2) ◽  
Author(s):  
Sarah J. Glastras ◽  
Hui Chen ◽  
Carol A. Pollock ◽  
Sonia Saad
Keyword(s):  
Metabolic Disease ◽  
Kidney Disease ◽  
Maternal Obesity ◽  
Disease Risk ◽  
Reproductive Age ◽  
Intrauterine Environment ◽  
Alcoholic Fatty Liver ◽  
Increased Risk ◽  
Epigenetic Modulation

Obesity, together with insulin resistance, promotes multiple metabolic abnormalities and is strongly associated with an increased risk of chronic disease including type 2 diabetes (T2D), hypertension, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). The incidence of obesity continues to rise in astronomical proportions throughout the world and affects all the different stages of the lifespan. Importantly, the proportion of women of reproductive age who are overweight or obese is increasing at an alarming rate and has potential ramifications for offspring health and disease risk. Evidence suggests a strong link between the intrauterine environment and disease programming. The current review will describe the importance of the intrauterine environment in the development of metabolic disease, including kidney disease. It will detail the known mechanisms of fetal programming, including the role of epigenetic modulation. The evidence for the role of maternal obesity in the developmental programming of CKD is derived mostly from our rodent models which will be described. The clinical implication of such findings will also be discussed.

scholarly journals Recruitment of APOL1 kidney disease risk variants to lipid droplets attenuates cell toxicity

2019 ◽  
Vol 116 (9) ◽  
pp. 3712-3721 ◽  
Author(s):  
Justin Chun ◽  
Jia-Yue Zhang ◽  
Maris S. Wilkins ◽  
Balajikarthick Subramanian ◽  
Cristian Riella ◽  
...  
Keyword(s):  
Cell Death ◽  
Kidney Disease ◽  
Lipid Droplets ◽  
Disease Risk ◽  
Significant Proportion ◽  
Autophagic Flux ◽  
Cell Toxicity ◽  
Risk Variant ◽  
Risk Variants ◽  
Increased Risk

Two coding variants in the apolipoprotein L1 (APOL1) gene (termed G1 and G2) are strongly associated with increased risk of nondiabetic kidney disease in people of recent African ancestry. The mechanisms by which the risk variants cause kidney damage, although not well-understood, are believed to involve injury to glomerular podocytes. The intracellular localization and function of APOL1 in podocytes remain unclear, with recent studies suggesting possible roles in the endoplasmic reticulum (ER), mitochondria, endosomes, lysosomes, and autophagosomes. Here, we demonstrate that APOL1 also localizes to intracellular lipid droplets (LDs). While a large fraction of risk variant APOL1 (G1 and G2) localizes to the ER, a significant proportion of wild-type APOL1 (G0) localizes to LDs. APOL1 transiently interacts with numerous organelles, including the ER, mitochondria, and endosomes. Treatment of cells that promote LD formation with oleic acid shifted the localization of G1 and G2 from the ER to LDs, with accompanying reduction of autophagic flux and cytotoxicity. Coexpression of G0 APOL1 with risk variant APOL1 enabled recruitment of G1 and G2 from the ER to LDs, accompanied by reduced cell death. The ability of G0 APOL1 to recruit risk variant APOL1 to LDs may help explain the recessive pattern of kidney disease inheritance. These studies establish APOL1 as a bona fide LD-associated protein, and reveal that recruitment of risk variant APOL1 to LDs reduces cell toxicity, autophagic flux, and cell death. Thus, interventions that divert APOL1 risk variants to LDs may serve as a novel therapeutic strategy to alleviate their cytotoxic effects.

scholarly journals Development and validation of a new chronic kidney disease risk equation: the role of pulse pressure

2013 ◽  
Vol 34 (suppl 1) ◽  
pp. P916-P916
Author(s):  
R. Ayyagari ◽  
F. Vekeman ◽  
E. Faust ◽  
S. Ong ◽  
A. Trahey ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Pulse Pressure ◽  
Disease Risk ◽  
Risk Equation ◽  
Chronic Kidney Disease Risk ◽  
Development And Validation

scholarly journals UBD modifies APOL1-induced kidney disease risk

2018 ◽  
Vol 115 (13) ◽  
pp. 3446-3451 ◽  
Author(s):  
Jia-Yue Zhang ◽  
Minxian Wang ◽  
Lei Tian ◽  
Giulio Genovese ◽  
Paul Yan ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Disease Risk ◽  
African Ancestry ◽  
Genetic Modifiers ◽  
Cell Toxicity ◽  
Mapping Study ◽  
Risk Alleles ◽  
Inflammatory Stimuli ◽  
Coding Variants ◽  
Apolipoprotein L1

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. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype.

scholarly journals Association of FMO3 Variants with Blood Pressure in the Atherosclerosis Risk in Communities Study

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Tyler S. Bryant ◽  
Priya Duggal ◽  
Bing Yu ◽  
Alanna C. Morrison ◽  
Tariq Shafi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
African Americans ◽  
Exome Sequencing ◽  
Meta Analysis ◽  
African Ancestry ◽  
Low Frequency ◽  
Atherosclerosis Risk In Communities ◽  
European Americans ◽  
Atherosclerosis Risk ◽  
Nitrogen Containing Compounds

Flavin containing monooxygenase 3 [FMO3] encodes dimethylaniline monooxygenase [N-oxide-forming] 3, which breaks down nitrogen-containing compounds, and has been implicated in blood pressure regulation. Studies have reported conflicting results of the association of a common nonsynonymous variant, E158K (rs2266782), with hypertension. We examined the associations of E158K, along with rare and low frequency exonic variants (minor allele frequency [MAF]<5%) in FMO3 with hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP). We included 7,350 European Americans and 2,814 African Americans in the Atherosclerosis Risk in Communities (ARIC) study with exome sequencing of FMO3. The association of FMO3 variants with SBP and DBP was tested using single variant and gene-based tests followed by the replication or interrogation of significant variants in ancestry-specific cohorts based on Bonferroni corrected thresholds. E158K had significant association with higher SBP in African Americans in ARIC (p=0.03), and two low frequency variants had significant association with higher SBP in African Americans (rs200985584, MAF 0.1%, p=0.0003) and European Americans (rs75904274, MAF 1.7%, p=0.006). These associations were not significant with additional samples: E158K in a meta-analysis of SBP of African ancestry (N=30,841, p=0.43) that included ARIC participants and the two low frequency variants in an independent ancestry-specific exome sequencing study of blood pressure (rs200985584, p=0.94; rs75904274, p=0.81). Our study does not support the association of E158K and low frequency variants in FMO3 with blood pressure and demonstrates the importance of replication in genetic studies.

Risk Factors for Infection Following Total Wrist Arthroplasty and Arthrodesis: An Analysis of 6641 Patients

Hand ◽  
2019 ◽  
pp. 155894471989003
Author(s):  
Alyssa D. Althoff ◽  
Russell A. Reeves ◽  
Sophia A. Traven ◽  
Harris S. Slone ◽  
D. Nicole Deal ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Postoperative Infection ◽  
Disease Risk ◽  
International Classification Of Diseases ◽  
Posttraumatic Arthritis ◽  
Nationally Representative ◽  
Wrist Arthroplasty

Background: Infection following wrist arthroplasty (WA) or wrist fusion (WF) is an uncommon but difficult complication often resulting in explantation and prolonged courses of antibiotics. The purposes of this study are to: (1) characterize the demographic trends of individuals undergoing WA and WF; (2) determine the incidence of postoperative infection; and (3) identify risk factors for postoperative infection. Methods: The PearlDiver database was used to query 100% Medicare Standard Analytic files from 2005 to 2014. Patients undergoing WA or radiocarpal WF were identified using Current Procedural Terminology (CPT) codes. Diagnosis for infection within 1 year of operative intervention was assessed by International Classification of Diseases, Ninth Revision codes or CPT codes related to infection. Multivariable logistic regression analyses were performed to evaluate the risk factors for postoperative infection. Results: Of the 6641 patients included, 1137 (17.1%) underwent arthroplasty and 5504 (82.9%) underwent arthrodesis. Within 1 year of the index procedure, 3.5% had a diagnosis of, or procedure for, postoperative infection (WA: n = 40 of 1137; WF: n = 192 of 5504). Risk factors for infection following WA include age >85, tobacco use, depression, diabetes mellitus, and chronic kidney disease. Risk factors following radiocarpal WF include male sex, age >85, body mass index <19 kg/m2, depression, diabetes mellitus, and chronic kidney disease. Posttraumatic origin of wrist arthritis was a risk factor for infection following both WA and WF. Conclusions: Infection following WA and WF is relatively uncommon in a nationally representative Medicare database cohort. Risk factors common to both WA and WF include age >85, depression, diabetes mellitus, chronic kidney disease, and posttraumatic arthritis.

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