Apolipoprotein L1 High-risk Genotypes Research Articles

APOL1 risk genotype in Europe: Data in patients with focal segmental glomerulosclerosis and after renal transplantation

Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis in populations with African ancestry. We determined the frequency of G1/G2 variants in patients with steroid-resistant nephrotic syndrome/focal segmental glomerulosclerosis with African or French West Indies origin in France and its relationships with other steroid-resistant nephrotic syndrome genes. In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped: the two risk allele (high risk) genotype was found in 43.1% of subjects compared to 18.9% in a control population (P<0.0001). Compared to patients in the low risk group, patients in the high-risk group were more likely to originate from French West Indies than from Africa. APOL1 high-risk genotype was more frequent in young adult patients, but it was also found in children and it was associated with a bad renal prognosis. APOL1 high-risk genotype was usually not associated with other causative mutation in known monogenic steroid-resistant nephrotic syndrome genes and families in which multiple individuals have focal segmental glomerulosclerosis may have APOL1-associated disease. After renal transplantation, recipients of deceased-donor kidney transplantation from individuals with recent African ancestry possessing two APOL1 high-risk variants have slightly shorter allograft survival. Effects of APOL1 are independent of other traditional risk factors. Recently it was shown that black living kidney donors homozygous for APOL1 high-risk alleles have significantly lower glomerular filtration rate and increased risk of end-stage renal disease after donation. However, APOL1 genotype may not summarize by itself the totality of this risk. We showed that living kidney donors of African ancestry in France with low-risk APOL1 genotype have lower postdonation eGFR increase and lower baseline kidney volume compared to Caucasian donors.

Mechanisms of Injury in APOL1-associated Kidney Disease.

An improved understanding of the pathogenesis in apolipoprotein L1 (APOL1) gene-associated chronic kidney disease (CKD) arose from observations in kidney transplantation. APOL1 genotyping could soon improve the safety of living kidney donation in individuals with recent African ancestry and alter the allocation of deceased donor kidneys. This article reviews the potential mechanisms that underlie development of APOL1-associated nephropathy. Roles for circulating APOL1 protein versus intrinsic renal expression of APOL1 are discussed, as well as the requirement for modifying genetic and/or environmental factors. Abundant evidence supports local kidney production of APOL1 renal-risk variant protein in the development of nephropathy; this is true in both native kidney disease and after renal transplantation. Only a minority of kidneys from individuals with APOL1 high-risk genotypes will develop CKD or manifest shorter renal allograft survival after transplantation. Therefore, modifying factors that explain why only a subset of kidneys develops nephropathy remain critical to identify. It appears likely that environmental exposures, as opposed to major APOL1-second gene interactions, will prove to be stronger modifiers of the risk for nephropathy. The evolving understanding of the pathogenesis in APOL1-associated nephropathy will identify biomarkers predicting nephropathy in individuals at high genetic risk and lead to novel therapies to prevent or slow native CKD progression and prolong survival of transplanted kidneys. In the interim, the National Institutes of Health-sponsored "APOL1 Long-term Kidney Transplantation Outcomes" Network will determine whether APOL1 genotyping in individuals with recent African ancestry improves outcomes and safety in kidney transplantation.

G1 is the major APOL1 risk allele for hypertension-attributed nephropathy in Central Africa.

BackgroundSub-Saharan Africans exhibit a higher frequency of chronic kidney disease (CKD) than other populations. In this study, we sought to determine the frequency of apolipoprotein L1 (APOL1) genotypes in hypertension-attributed CKD in Kinshasa, Democratic Republic of the Congo.MethodsWe performed a case–control study identifying 162 subjects: 79 with hypertension-attributed CKD and 83 controls living in Kinshasa who were genotyped for APOL1 risk variants between July 2013 and November 2016. We selected control subjects from the general population and matched them with the cases according to age. Logistic regression analysis was used to examine the relationship between APOL1 high-risk genotypes and CKD.ResultsThe frequencies of the APOL1 G1 and G2 alleles were 19.1 and 7.1%, respectively. The number of individuals with the G1 and G2 risk alleles was significantly higher in the CKD group (12.7%) than in the control group (2.4%), particularly in individuals with end-stage kidney disease (14.3%). Subjects carrying two risk alleles was strongly and independently associated with hypertension-attributed nephropathy, with an adjusted odds ratio of 7.7 (95% confidence interval 1.5–39.7; P = 0.014). The high-risk APOL1 genotypes were G1/G1 and G1/G2, whereas G2/G2 was not found in the study population.ConclusionsThe results of this study demonstrate the association of high-risk APOL1 genotypes with kidney disease in Kinshasa. The absence of G2/G2 may be consistent with powerful selective sweeps induced by Trypanosoma brucei gambiense infection. In contrast, the presence of APOL1 G2/G2 among individuals of African ancestry in the USA may indicate relaxation of natural selection in a trypanosome-free environment.

Gene for preeclampsia

Health Preeclampsia is a serious complication of pregnancy that often presents as an increase in maternal blood pressure. The disorder is more prevalent and severe in women with African ancestry, most likely because of genetic factors. Reidy et al. have been investigating a variant of the gene encoding apolipoprotein L1 ( APOL1 ), which was previously shown to confer a high risk of kidney disease in black Americans. Studying two independent populations of pregnant black women, they found that preeclampsia was associated with the APOL1 high-risk genotype. Interestingly, it was the genotype of the fetus, not the mother, that mattered. The fetal APOL1 high-risk genotype may be linked to one in eight cases of preeclampsia in black women. Am. J. Hum. Genet. 103 , 367 (2018).

Fetal—Not Maternal—APOL1 Genotype Associated with Risk for Preeclampsia in Those with African Ancestry

Black Americans are at increased risk for preeclampsia. Genetic variants in apolipoprotein L1 (APOL1) account for much of the increased risk for kidney disease in blacks. APOL1 is expressed in human placenta and transgenic mice expressing APOL1 develop preeclampsia. We evaluated the role of APOL1 variants in human preeclampsia. We determined maternal and fetal APOL1 genotypes in black women with preeclampsia in two populations. At Einstein Montefiore Center (EMC) Affiliated Hospitals, we studied 121 pregnancies in black women with preeclampsia. At University of Tennessee Health Science Center (UTHSC), we studied 93 pregnancies in black women with preeclampsia and 793 pregnancies without preeclampsia. We measured serum markers of preeclampsia soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng). Fetal APOL1 high-risk (HR) genotype was associated with preeclampsia, with odds ratios at EMC and UTHSC of 1.84 (95% CI 1.11, 2.93) and 1.92 (95% CI 1.05, 3.49), respectively. Maternal APOL1 HR genotype was not associated with preeclampsia. Mothers with the fetal APOL1 HR genotype had more cerebral or visual disturbances (63% versus 37%, p = 0.04). In addition, fetal APOL1 HR genotype was associated with a higher sFLT-1/PlGF ratio at birth (p = 0.04). Fetal APOL1 high-risk genotype increases the risk for preeclampsia, likely by adversely affecting placental function. Further research is needed to assess whether APOL1 genetic testing can predict preeclampsia and improve pregnancy outcomes.

APOL1 Nephropathy Risk Variants and Incident Cardiovascular Disease Events in Community-Dwelling Black Adults.

APOL1 renal risk variants are strongly associated with chronic kidney disease in Black adults, but reported associations with cardiovascular disease (CVD) have been conflicting. We examined associations of APOL1 with incident coronary heart disease (n=323), ischemic stroke (n=331), and the composite CVD outcome (n=500) in 10 605 Black participants of the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Primary analyses compared individuals with APOL1 high-risk genotypes to APOL1 low-risk genotypes in Cox proportional hazards models adjusted for CVD risk factors and African ancestry. APOL1 high-risk participants were younger and more likely to have albuminuria at baseline than APOL1 low-risk participants. The risk of incident stroke, coronary heart disease, or composite CVD end point did not significantly differ by APOL1 genotype status in multivariable models. The association of APOL1 genotype with incident composite CVD differed by diabetes mellitus status (Pinteraction=0.004). In those without diabetes mellitus, APOL1 high-risk genotypes associated with greater risk of incident composite CVD (hazard ratio, 1.67; 95% confidence interval, 1.12-2.47) compared with those with APOL1 low-risk genotypes in multivariable adjusted models. This latter association was driven by ischemic strokes (hazard ratio, 2.32; 95% confidence interval, 1.33-4.07), in particular, those related to small vessel disease (hazard ratio, 5.10; 95% confidence interval, 1.55-16.56). There was no statistically significant association of APOL1 genotypes with incident CVD in subjects with diabetes mellitus. The APOL1 high-risk genotype was associated with higher stroke risk in individuals without but not those with chronic kidney disease in fully adjusted models. APOL1 high-risk status is associated with CVD events in community-dwelling Black adults without diabetes mellitus.

Association of Apolipoprotein L-1 polymorphisms with blood pressure in three multi-ethnic African studies

# Background Genetic variants in the Apolipoprotein L1 (APOL1) gene greatly increase risk for chronic kidney disease in African Americans. We hypothesized that the APOL1 renal risk alleles would be associated with higher blood pressure in Africans. # Methods We used data from three multi-ethnic, population-based studies from Kenya, Ghana, and Nigeria to examine the association between ethnic group prevalence of APOL1 risk variants and blood pressure. Using available genotype data, we were able to link ethnic group status to APOL1 risk variant frequency in 10 423 persons. # Results Age, sex, body mass index, and frequency of the APOL1 high-risk genotype (two risk alleles) were associated with mean systolic blood pressure (SBP). In the adjusted model, a 1% higher prevalence of the APOL1 risk genotype was associated with 0.18 mmHg (95% confidence interval CI 0.05-0.32) higher systolic blood pressure (SBP). # Conclusions Mean SBP was 5 mmHg higher in African ethnic groups where nearly a third of persons carry two high risk APOL1 alleles, compared with ethnic groups where homozygosity is rare. Since uncontrolled blood pressure predisposes to high risks for death and substantial disability prior to development of end-stage kidney disease, studies exploring the link between the APOL1 risk alleles and blood pressure are crucial to understanding the full implications of APOL1 genetic variation in Africa.

Apolipoprotein L1 Genetic Variants Are Associated with Evidence of Early Kidney Injury in Sickle Cell Disease

▪Background and Objectives: Apolipoprotein L1 (APOL1) renal risk variants prevalent in African-ancestry populations are associated with chronic kidney disease (CKD). CKD is a major cause of morbidity and mortality in sickle cell disease (SCD) in adults; yet the prevalence and significance of APOL1 renal-risk variants in this population remains unknown. Our objective was to determine expression of biomarkers of early kidney disease in African American youth with SCD, based on their APOL1 genotype.Methods:We enrolled65 African American subjects between 5 to 21 years of age with SCD (Hb SS or Hb S β0 thalassemia). Blood and concurrent urine samples were collected. Allenrolled subjects underwent APOL1 genotyping by PCR analysis of DNA extracted from whole blood. Presence of two renal-risk variants qualified for APOL1 High Risk (HR) genotype, while presence of zero or one copy of renal-risk variants qualified for APOL1 Low Risk (LR) genotype.Results: APOL1 HR genotype was expressed by 22% of our subjects; this is comparable to 23% prevalence of APOL1 HR genotype in African American adults with CKD (AASK study). Both groups were similar with respect to distribution of age, BMI z-scores, renal function and urine osmolality. Hyperfiltration was noted in both groups based on low serum creatinine for age, and elevated eGFR based on creatinine clearance. However, median urine albumin excretion rate was significantly higher in HR group vs. LR group.Conclusions: Preliminary data in this cohort of 65 children and adolescents with SCD detected greater urine albumin excretion rate in the presence of APOL1 HR genotype. Screening SCD youth for heightened CKD risk may be an avenue to initiate targeted preventive interventions to preserve renal function and reduce progression of kidney disease.Acknowledgment: Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number P20GM109021; National Kidney Foundation Young Investigator Grant and DE-CTR-ACCEL grant number U54-GM104941 (PI: Binder-Macleod). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Combined Effects of GSTM1 Null Allele and APOL1 Renal Risk Alleles in CKD Progression in the African American Study of Kidney Disease and Hypertension Trial.

Apolipoprotein L-1 (APOL1) high-risk alleles and the glutathione-S-transferase-μ1 (GSTM1) null allele have been shown separately to associate with CKD progression in the African American Study of Kidney Disease and Hypertension (AASK) trial participants. Here, we determined combined effects of GSTM1 null and APOL1 high-risk alleles on clinical outcomes in 682 AASK participants who were classified into four groups by GSTM1 null or active genotype and APOL1 high- or low-risk genotype. We assessed survival differences among these groups by log-rank test and Cox regression adjusted for important clinical variables for time to GFR event (change in GFR of 50% or 25-ml/min per 1.73 m2 decline), incident ESRD, death, or composite outcomes. The groups differed significantly in event-free survival for incident ESRD and composite outcomes (P≤0.001 by log-rank test). Compared with the reference GSTM1 active/APOL1 low-risk group, other groups had these hazard ratios for the composite outcome of incident ESRD and change in GFR: GSTM1 active/APOL1 high-risk hazard ratio, 2.13; 95% confidence interval, 0.76 to 5.90 (P=0.15); GSTM1 null/APOL1 low-risk hazard ratio, 2.05; 95% confidence interval, 1.08 to 3.88 (P=0.03); and GSTM1 null/APOL1 high-risk hazard ratio, 3.0; 95% confidence interval, 1.51 to 5.96 (P=0.002). In conclusion, GSTM1 null and APOL1 high-risk alleles deleteriously affect CKD progression among blacks with hypertension, and subjects with both GSTM1 null and APOL1 high-risk genotypes had highest risk of adverse renal outcomes. Larger cohorts are needed to fully explore interactions of GSTM1 and APOL1 genotypes in other subgroups.

Examination of Potential Modifiers of the Association of APOL1 Alleles with CKD Progression.

Common apolipoprotein L1 (APOL1) variants are associated with increased risk of progressive CKD; however, not all individuals with high-risk APOL1 variants experience CKD progression. Identification of factors contributing to heterogeneity has important scientific and clinical implications. Using multivariable Cox models, we analyzed data from 693 participants in the African American Study of Kidney Disease and Hypertension to identify factors that modify the association between APOL1 genotypes and CKD progression (doubling of serum creatinine or incident ESRD). Participant mean age was 54 years old, median GFR was 49 ml/min per 1.73 m(2), and 23% had the APOL1 high-risk genotype (two copies of the high-risk allele). Over a mean follow-up of 7.8 years, 288 (42%) participants experienced CKD progression. As previously reported, the high-risk genotype was associated with higher risk of CKD progression compared with the low-risk genotype (hazard ratio [HR], 1.88; 95% confidence interval [95% CI], 1.46 to 2.41). Although we found some suggestion that obesity (HR, 1.48; 95% CI, 1.05 to 2.08 and HR, 2.44; 95% CI, 1.66 to 3.57 for body mass index ≥ 30 versus <30 kg/m(2); P interaction =0.04) and increased urinary excretion of urea nitrogen (HR, 1.43; 95% CI, 0.98 to 2.09 versus HR, 2.33; 95% CI, 1.65 to 3.30 for urine urea nitrogen ≥ 8 versus <8 g/d; P interaction =0.04) were associated with lower APOL1-associated risk for CKD progression, these findings were not robust in sensitivity analyses with alternative cut points. No other sociodemographic (e.g., education and income), clinical (e.g., systolic BP and smoking), or laboratory (e.g., net endogenous acid production, urinary sodium and potassium excretions, 25-hydroxy vitamin D, intact parathyroid hormone, or fibroblast growth factor 23) variables modified the association between APOL1 and CKD progression (P interaction >0.05 for each). Sociodemographic factors and common risk factors for CKD progression do not seem to alter APOL1-related CKD progression. Additional investigation is needed to identify nontraditional factors that may affect the association between APOL1 and progressive CKD.

Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1

Apolipoprotein L1 (APOL1) risk variants greatly elevate the risk of kidney disease in African Americans. Here we report a cohort of patients who developed collapsing focal segmental glomerulosclerosis while receiving therapeutic interferon, all of whom carried the APOL1 high-risk genotype. This finding raised the possibility that interferons and the molecular pattern recognition receptors that stimulate interferon production may contribute to APOL1-associated kidney disease. In cell culture, interferons and toll-like receptor agonists increased APOL1 expression by up to 200-fold, in some cases with the appearance of transcripts not detected under basal conditions. PolyI:C, a double-stranded RNA TLR3 agonist, increased APOL1 expression by upregulating interferons directly or through an interferon-independent, IRF-3 dependent pathway. Using pharmacological inhibitors, shRNA knockdown, and chromatin immunoprecipitation, we found that the interferon-independent TLR3 pathway relied on signaling through TBK1, NF-kB, and Jak kinases, and on binding of IRF1, IRF2, and STAT2 at the APOL1 transcription start site. We also demonstrate that overexpression of the APOL1 risk variants is more injurious to cells than overexpression of the wild-type APOL1 protein. Our study illustrates that anti-viral pathways may be an important inducer of kidney disease in individuals with the APOL1 high-risk genotype and identifies potential targets for prevention or treatment.