APOL1 genetic variants, chronic kidney diseases and hypertension in mixed ancestry South Africans.
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ABSTRACT:
SUBMITTER: Matsha TE
PROVIDER: S-EPMC4482162 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
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Project description:Uromodulin, the most abundant protein in urine, is synthesized in the thick ascending loop of Henle and distal convoluted tubules. Patients with chronic kidney disease (CKD) have reduced urinary uromodulin levels secondary to tubular damage. Genome wide association studies identified significant single nucleotide polymorphism (SNP) associations with CKD at the uromodulin (UMOD) locus. We examined the association of urinary uromodulin concentrations with CKD and with SNP rs1333226 in the UMOD gene. The study included 71 black South Africans with hypertension-attributed CKD with an eGFR ≤ 60ml/min/1.73m2, 52 first-degree relatives, and 58 unrelated controls. Urinary uromodulin concentration was measured using Luminex® multiplex kits. After DNA extraction from blood using the Maxwell® automated platform, genotyping of rs13333226 was performed using real-time PCR using TaqMan® genotyping assays. Urinary uromodulin levels were significantly lower in CKD cases compared to both controls and first-degree relatives and correlated negatively with age, serum uric acid, serum creatinine, and systolic BP and positively with CKD-EPI eGFR. For each 1-standard deviation increase in uromodulin level, the multivariable-adjusted odds ratio for CKD was 0.6 (95% CI [0.48 to 0.81]; p <0.01). There were no significant differences in the minor allele frequency between CKD cases and controls (p = 0.59) nor between first-degree relatives and controls (p = 0.98). There were no significant associations between genotype at rs13333226 and urine uromodulin levels (p = 0.43). Higher levels of urinary uromodulin are associated with lower odds of hypertension-attributed CKD. We did not detect associations of genotype at rs13333226 with urinary uromodulin levels in our sample population. Larger sample size studies from ethnically disparate populations are essential to further categorize this association.
| S-EPMC6466913 | biostudies-literature
Project description:APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a South-African black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polymorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV-associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV-associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P<0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy-naïve South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa.
| S-EPMC4625661 | biostudies-literature
Project description:IntroductionThe polyomaviruses, John Cunningham (JC) and BK, infect humans, with primary infection occurring in childhood. First-degree relatives of African American individuals with nondiabetic chronic kidney disease (CKD) who had 2 apolipoprotein L1 (APOL1) risk variants had a lower prevalence of kidney disease in the presence of JC viruria. This study determined the prevalence of polyomavirus infections and their effects, in the presence APOL1 risk alleles, on CKD.MethodsSixty-four black South African individuals with hypertension-attributed CKD with an estimated glomerular filtration rate (eGFR) ≤60 ml/min per 1.73 m2, 44 first-degree relatives, and 56 unrelated controls were included. Viral DNA was extracted from urine and genomic DNA from blood using the Maxwell automated platform. Viral-load quantification was determined using Genesig polyomavirus kits. Genotyping of the APOL1 G1 and G2 variants was by polymerase chain reaction-restriction fragment length polymorphism.ResultsThe prevalence of JC viruria was significantly higher in controls (36%) and first-degree relatives (20%) than in patients with CKD (3%, P < 0.001). Although patients with CKD and their first-degree relatives had similar socioeconomic status scores, we found a lower prevalence of JC viruria in patients with CKD compared with their first-degree relatives, who had normal kidney function. The absence of John Cunningham virus (JCV), DNA was a strong predictor of CKD (odds ratio [OR] 43.43; 95% confidence interval [CI] 7.39-255.20; P < 0.001).ConclusionThere was a strong association between the absence of JC viruria and CKD. Studies with a larger sample are essential to determine the renoprotective effects of JCV and its interactions with APOL1.
| S-EPMC6611950 | biostudies-literature
Project description:BackgroundAmong patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.MethodsIn two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline.ResultsIn the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons).ConclusionsRenal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
| S-EPMC3969022 | biostudies-literature
Project description:ObjectivesThe objectives were to characterise the haematological profile of screen-detected chronic kidney disease (CKD) participants and to correlate the complete blood count measures with the commonly advocated kidney function estimators.MethodsThe current cross-sectional study used data, collected between February 2015 and November 2016, of 1564 adults of mixed-ancestry, who participated in the Cape Town Vascular and Metabolic Health study. Kidney function was estimated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. CKD was defined as estimated glomerular filtration rate (eGFR) <60?mL/min/1.73?m2, and anaemia as haemoglobin level <13.5?g/dL (men) and <12?g/dL (women).ResultsBased on the MDRD and CKD-EPI equations, the crude prevalence of CKD was 6% and 3%. Irrespective of the equation used, median red blood cell (RBC) indices were consistently lower in those with CKD compared with those without CKD (all p<0.0001). Despite not showing any significant difference in total white blood cell (WBC) count between the two groups, the number of lymphocytes were lower (p=0.0001?and p<0.0001 for MDRD and CKD-EPI, respectively) and neutrophil count (both p<0.0297) and the ratio of lymphocytes to neutrophil (both p<0.0001) higher in the CKD group compared with those without CKD; with the remaining WBC indices similar in the two groups. The platelet count was similar in both groups. Of the screen-detected CKD participants, 45.5% (MDRD) and 57.8% (CKD-EPI) were anaemic, with the prevalence increasing with increasing severity of CKD, from 37.2% (stage 3) to 82.4% (stages 4-5). Furthermore, CKD-EPI-estimated kidney function, but not MDRD, was positively associated with RBC indices.ConclusionThough it remains unclear whether common kidney function estimators provide accurate estimates of CKD in Africans, the correlation of their estimates with deteriorating RBC profile, suggests that advocated estimators, to some extent approximate kidney function in African populations.
| S-EPMC6231601 | biostudies-literature
Project description:BackgroundCombining HbA1c with glycated albumin (GA) may improve detection of dysglycaemia. As BMI correlates positively with HbA1c and negatively with GA, HbA1c may be more effective in obese and GA in nonobese individuals.MethodsTo relate these findings to Africans, we assessed in 1274 South Africans living in CapeTown (male 26%; age 48±16y; BMI 28.7 kg/m2 (range 15.6-73.8); obesity 39.9% and no prior diabetes history) the: (1) correlation of BMI with HbA1c and GA, (2) ability of HbA1c and GA separately and jointly, to detect OGTT-diagnosed dysglycaemia (diabetes plus prediabetes). Data collection took place between 2014 and 2016 in the City of Cape Town. Dysglycaemia was diagnosed by glucose criteria for the OGTT. Youden index was used to optimize diagnostic thresholds for HbA1c and GA.FindingsNormal glucose tolerance, prediabetes and diabetes occurred in 76%, 17% and 7%, respectively. BMI positively correlated with HbA1c [r = 0·34 [95%CI: 0·29,0·39)] and negatively with GA [-0·08 (0·13,0·03)]. For HbA1c the optimal threshold by Youden-index for dysglycaemia diagnosis was: 6·0% (95%CI: 5·8,6·2) and for GA: 13·44% (12·72,14·71). In the nonobese, obese and total cohort, HbA1c-alone detected: 51% (42-60), 72% (65,78), 63% (57,68), respectively; GA-alone detected 55% (52% (46,63), 52% (44, 59) and 53% (47,53), respectively; whereas: HbA1c+GA detected: 69% (60,76), 82% (75,87) and 76% (71, 81). Therefore, for the total cohort detection of dysglycaemia HbA1c-alone vs HbA1c+GA detected 63% (57,68) vs 76% (71,81).InterpretationThe opposite correlations of HbA1c and GA with BMI have now been demonstrated in an African-based population. Improving detection of dysglycaemia by combining HbA1c and GA has important implications for diabetes risk screening.FundingAES is supported by the intramural programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Minority Health and Health Disparities of the National Institutes of Health (NIH, Bethesda, Maryland, USA). DBS is supported by the intramural program of the Clinical Center of NIH. The South African Medical Research Council (SAMRC) funded the VMH study with funds from the National Treasury under its Economic Competitiveness and Support Package (MRC-RFA-UFSP-01-2013/VMH Study).
| S-EPMC9249545 | biostudies-literature
Project description:Recent studies have identified genetic variants in APOL1 that may contribute to the increased incidence of kidney disease in populations with African ancestry. Here, we review the biology of APOL1 present in the circulation and localized to the kidney as it may contribute to the pathogenesis of APOL1-associated kidney disease.
| S-EPMC4022720 | biostudies-literature
Project description:Background: The concept of obesity phenotypes encompasses a different approach to evaluating the relationship between obesity and cardiometabolic diseases. Considering the minimal research on obesity phenotypes in Africa, we investigated these changes from 2008/09 to 2014/16 in the mixed ancestry population in Cape Town, South Africa. Methods: In all, 928 (2008/09) and 1969 (2014/16) ≥20 year old participants were included in two community-based cross-sectional studies. For obesity phenotype classification, a combination of body mass index (BMI) categories and prevalent cardiometabolic disease risk factors were used, with the presence of ≥2 cardiometabolic abnormalities defining abnormal metabolic status. Interaction tests were used to investigate changes in their distribution across the years of study. Results: Distribution of BMI categories differed significantly between the 2 years; normal weight, overweight and obese: 27.4, 27.4, and 45.3% in 2008/09 vs. 34.2, 23.6, and 42.2% in 2014/16 (p = 0.001). There was no differential effect in the distribution of obesity phenotypes pattern across the two time-points (interaction p = 0.126). Across BMI categories, levels of cardiometabolic risk factors linearly deteriorated in both metabolically healthy and abnormal participants (all p ≤ 0.018 for linear trends). Findings were not sensitive to the number of metabolic abnormalities included in the definition of obesity phenotypes. Conclusions: Our study showed negligible differences in obesity phenotypes over time, but a high burden of metabolic abnormalities among normal weight participants, and a significant proportion of metabolically health obese individuals. Further investigation is needed to improve risk stratification and cost-effective identification of individuals at high risk for cardiometabolic diseases.
| S-EPMC6851026 | biostudies-literature
Project description:Background and objectivesThe APOL1 risk variants (G1 and G2) are associated with kidney disease among Black adults, but the clinical presentation is heterogeneous. In mouse models and cell systems, increased gene expression of G1 and G2 confers cytotoxicity. How APOL1 risk variants relate to the circulating proteome warrants further investigation.Design, setting, participants, & measurementsAmong 461 African American Study of Kidney Disease and Hypertension (AASK) participants (mean age: 54 years; 41% women; mean GFR: 46 ml/min per 1.73 m2), we evaluated associations of APOL1 risk variants with 6790 serum proteins (measured via SOMAscan) using linear regression models. Covariates included age, sex, percentage of European ancestry, and protein principal components 1-5. Associated proteins were then evaluated as mediators of APOL1-associated risk for kidney failure. Findings were replicated among 875 Atherosclerosis Risk in Communities (ARIC) study Black participants (mean age: 75 years; 66% women; mean eGFR: 67 ml/min per 1.73 m2).ResultsIn the AASK study, having two (versus zero or one) APOL1 risk alleles was associated with lower serum levels of APOL1 (P=3.11E-13; P=3.12E-06 [two aptamers]), APOL2 (P=1.45E-10), CLSTN2 (P=2.66E-06), MMP-2 (P=2.96E-06), SPOCK2 (P=2.57E-05), and TIMP-2 (P=2.98E-05) proteins. In the ARIC study, APOL1 risk alleles were associated with APOL1 (P=1.28E-11); MMP-2 (P=0.004) and TIMP-2 (P=0.007) were associated only in an additive model, and APOL2 was not available. APOL1 high-risk status was associated with a 1.6-fold greater risk of kidney failure in the AASK study; none of the identified proteins mediated this association. APOL1 protein levels were not associated with kidney failure in either cohort.ConclusionsAPOL1 risk variants were strongly associated with lower circulating levels of APOL1 and other proteins, but none mediated the APOL1-associated risk for kidney failure. APOL1 protein level was also not associated with kidney failure.
| S-EPMC9269576 | biostudies-literature
Project description:Signing Deaf South Africans have limited access to health information. As a result, their knowledge about health is limited. Cell phone usage in South Africa is high. This study aimed to assess whether a short message service (SMS)-based health promotion campaign could improve Deaf people's knowledge of hypertension and healthy living. Additionally, the study aimed to assess the acceptability of using SMSs for health promotion targeting Deaf people.A baseline questionnaire assessed participants' knowledge about hypertension before an SMS-based information campaign was conducted. After the campaign, an exit questionnaire was conducted, containing the same questions as the baseline questionnaire with additional questions about general acceptability and communication preferences. Results were compared between baseline and exit, using McNemar's test, paired t-test and Wilcoxon signed-rank test. Focus groups aimed to get further information on the impact and acceptability of SMSs. The focus groups were analysed using inductive thematic analysis.The campaign recruited 82 participants for the baseline survey, but due to significant loss-to-follow-up and exclusions only 41 participants were included in the analysis of the survey. The majority (60%) were men. Eighty percent were employed, while 98% had not finished high school. The campaign showed a statistically significant improvement in overall knowledge about hypertension and healthy living amongst participants. Six individual questions out of 19 also showed a statistically significant improvement. Despite this, participants in focus groups found the medical terminology difficult to understand. Several ways of improving SMS campaigns for the Deaf were identified. These included using using pictures, using 'signed' SMSs, combining SMSs with signed drama and linking SMS-campaigns to an interactive communication service that would enable the Deaf to pose questions for clarification. Focus groups suggested that participants who were hypertensive during the campaign adopted a healthier lifestyle.SMSs were effective in improving Deaf people's knowledge of hypertension and healthy living. However, SMS-campaigns should be cognizant of Deaf people's unique needs and communication preference and explore how to accommodate these.The research was registered with the Pan African Clinical Trial Registry on December 1, 2015. Identification number: PACTR201512001353476 .
| S-EPMC5563060 | biostudies-other